DNA repair-related genes and adipogenesis: Lessons from congenital lipodystrophies

Abstract

Classical and progeroid congenital lipodystrophies are a collection of rare diseases displaying a large genetic heterogeneity. They occur due to pathogenic variants in genes associated with adipogenesis, DNA repair pathways, and genome stability. Subjects with lipodystrophy exhibit an impairment in the homeostasis of subcutaneous white adipose tissue (sWAT), resulting in low leptin and adiponectin levels, insulin resistance (IR), diabetes, dyslipidemia, ectopic fat deposition, inflammation, mitochondrial and endoplasmic reticulum commitments, among others. However, how pathogenic variants in adipogenesis-related genes modulate DNA repair in some classical congenital lipodystrophies has not been elucidated. In the same way, no data is clarifying how pathogenic variants in DNA repair genes result in sWAT loss in different types of progeroid lipodystrophies. This review will concentrate on the main molecular findings to understand the link between DNA damage/repair and adipogenesis in human and animal models of congenital lipodystrophies. We will focus on classical and progeroid congenital lipodystrophies directly or indirectly related to DNA repair pathways, highlighting the role of DNA repair-related proteins in maintaining sWAT homeostasis.

Keywords:
DNA repair; adipogenesis; genetic lipodystrophies; metabolism

Introduction

Nuclear and mitochondrial DNA are continuously exposed to damage induced by endogenous and exogenous sources (Evans et al., 2004; Bauer et al., 2015). Endogenous sources of DNA damage include reactive oxygen species (ROS) generated during normal cell metabolism, mainly by the mitochondria (Balaban et al., 2005), but also by the endoplasmic reticulum (ER), peroxisomes, and cell membrane (Bhattacharyya et al., 2014). Furthermore, exogenous DNA damage sources mainly include ultraviolet (UV) radiation, ionizing radiation (IRa), and alkylating agents (Evans et al., 2004).

Cells have developed several DNA repair pathways to defend the genome against different types of damage, including the most deleterious lesions, such as oxidized DNA lesions, single strand breaks (SSBs), and double-strand breaks (DSBs) (Limpose et al., 2017). DNA repair pathways protect from frequent lesions resulting in DNA breaks. Oxidized DNA lesions and SSBs are usually repaired by the base excision repair (BER); DSBs are repaired by homologous recombination (HR) and non-homologous end joining (NHEJ). Although nucleotide excision repair (NER) is mainly responsible for repairing bulky DNA-distorting lesions induced by UV radiation, this pathway is also involved with the repair of oxidized DNA lesions together with BER (Dianov et al., 1999; Stevnsner et al., 2002; Tuo et al., 2002; D’Errico et al., 2006; Stevnsner et al., 2008; de Melo et al., 2016; Kumar et al., 2020). There are two NER sub-pathways, global genomic-NER (GG-NER) and transcription-coupled NER (TC-NER), which differ only in the initial step of DNA lesion recognition.

Failure to repair DNA damage or misrepaired DNA lesions leads to genomic instability and changes in cellular homeostasis, resulting in cancer (Menck and Munford, 2014; Jeggo et al., 2016), neurodegenerative diseases (Weissman et al., 2007; Krasikova et al., 2021), aging (Schumacher et al., 2021), and progeroid diseases with loss of subcutaneous white adipose tissue (sWAT) (López-Otín et al., 2013; Araújo-Vilar and Santini, 2019; Araújo de Melo Campos et al., 2021). For example, in the progeroid Cockayne Syndrome (CS), defects in NER may lead to premature aging with loss of sWAT (László and Simon, 1986; Nance and Berry, 1992; Kamenisch et al., 2010). Aging is a process that disturbs most living cells and is related to the accretion of damage to the molecules, genomic instability, telomere dysfunction, heterochromatin loss, and loss of sWAT. Other hallmarks of aging include mitochondrial dysfunction, senescence, inflammation, deregulated nutrient sensing, and metabolic defects. Altogether, these changes lead to a failure in stem cell function, reducing their capabilities to regenerate tissue (Schosserer et al., 2018; Palmer et al., 2019; Smith et al., 2021).

Over the past decade, a renewed interest in adipose tissue functions and genomic integrity has emerged. Accumulation of senescent white adipocytes occurs during aging, which is associated with hypertrophy of adipocytes, dyslipidemia, and IR (Unger, 2005; Smith et al., 2021; Von Bank et al., 2021). Extreme decrease of sWAT and senescence of adipocytes are hallmarks of an advanced age (Tchkonia et al., 2010; Liu et al., 2018). During aging, the reduced capacity of sWAT to store lipids may contribute to metabolic complications due to ectopic deposition of lipids (lipotoxicity) (Von Bank, et al., 2021). The mechanisms involved in adipose tissue aging were recently reviewed (Ou et al., 2022). The main hallmarks of senescent cells are a secretory phenotype, cell cycle arrest, and activation of a DNA damage response (DDR), with phosphorylated histone H2AX (γ-H2AX) and p53 expression as markers of senescent cells (Tchkonia et al., 2010; Liu et al., 2018). Further, a lower expression of the H2AX gene was found in sWAT of obese individuals (Rohde et al., 2020). However, the link between senescence, DNA damage, and loss of sWAT in congenital lipodystrophies is poorly understood.

This review discusses recent molecular findings in the study of congenital lipodystrophies and the role of DNA repair in maintaining adipose tissue’s functions. We focused on human and animal models of congenital lipodystrophies to unravel the link between DNA damage/repair and sWAT homeostasis.

sWAT physiology and aging

White adipose tissue (WAT) has been extensively studied due to the association between increased visceral WAT (vWAT) and metabolic and cardiovascular disturbs (Tchkonia et al., 2010; Item and Konrad, 2012). On the contrary, studies concerning sWAT and brown adipose tissue (BAT) have shown their beneficial effects in improving metabolism and insulin sensitivity. These findings highlight that distinct WAT depots have different roles related to metabolic health. While vWAT is found around visceral organs, such as gonadal, retroperitoneal, perirenal, omental, and mesenteric localization, depots of sWAT have restricted localization and functions, being found mainly under the skin (metabolically active sWAT) and in palms and soles (mechanic sWAT) (Wajchenberg, 2000; Choe et al., 2016; Schosserer et al., 2018).

The primary interest of studies concerning WAT physiology was mainly directed to its role as an energy storage tissue. However, over the last years, WAT research has gained a lot of attention since WAT has an essential hormonal function and undergoes significant changes during aging (Ou et al., 2022). One of the proposed aging hallmarks is dysfunctional adipose tissue and the consequent metabolic defects, including a reduction in the levels of somatotrophic axis hormones, such as insulin-like growth factor 1 (IGF1) and growth hormone (GH), as well as steroid hormones (Carrero et al., 2016). Indeed, changes in redox homeostasis have been found in metabolic syndrome, obesity, type 2 diabetes mellitus (DM), and lipodystrophies. During aging, WAT suffers redistribution, BAT depots decrease, and adipose progenitor and stem cells (APSCs) decline. Further, dysfunctional smaller cells similar to adipocytes increase in aged WAT, which show reduced insulin sensitivity than fully differentiated adipocytes (Kirkland et al., 2002). Altogether, these age-related changes in adipose tissue result in decreased sWAT and increased vWAT depots, compromising body function. The pathophysiology of adipose tissue in lipodystrophies was remarkably discussed in recent reviews (Zammouri et al., 2021; Lim et al., 2021; Le Lay et al., 2022).

Classical and progeroid congenital lipodystrophies

Genetic lipodystrophies are a group of rare, heterogeneous metabolic diseases caused by a lack of sWAT, which can be total or partial (Garg, 2011; Brown et al., 2016; Zammouri et al., 2021; Araújo de Melo Campos et al., 2021). As in aging, congenital lipodystrophies have been associated with adipose tissue redistribution, sWAT loss, increased vWAT, and ectopic fat deposition (Garg and Agarwal, 2009; Zammouri et al., 2021). The nearly complete lack of body fat at birth results in Congenital Generalized Lipodystrophy (CGL), the most severe form of lipodystrophy. Instead, Familial Partial Lipodystrophy (FPLD) is characterized by a deficiency of sWAT in the limbs and gluteus that emerges during childhood or puberty, associated with fatty tissue deposition in specific body regions, such as the face, neck, and intra-abdominal area. Progeroid syndromes are also a group of rare congenital diseases characterized by clinical features including aging, hair loss, cardiovascular commitments, comorbidities affecting the skeleton and muscle, lipodystrophy, metabolic changes, and others (Van Der Pluijm et al., 2007; Turaga et al., 2009; Carrero et al., 2016). Since generalized or partial lipodystrophy is an important clinical finding associated with numerous progeroid diseases, treatment strategies have been developed to fight metabolic and mitochondrial commitments found in these syndromes (Carrero et al., 2016; Zammouri et al., 2021). In this review, we will focus only on classical and progeroid lipodystrophies associated with senescence, DNA damage accumulation, and metabolic dysfunction, three hallmarks of aging (López-Otín et al., 2013). Table 1 shows the main classical and progeroid congenital syndromes.

Table 1 -
The mains progeroid and classical inherited lipodystrophies.

Gene code (*OMIM code)	Protein name	Disease name / Degree of sWAT loss	Disease code (#OMIM code)	Adipose tissue commitment	Inheritance	Reference
Progeroid inherited lipodystrophies due to pathogenic variants mainly in genes associated with DNA repair and genomic stability.
POLR3A (*614258)	Polymerase III, RNA, subunit A	Wiedemann-Rautenstrauch Syndrome / Partial	WDRTS (#264090)	Progressive generalized loss of sWAT.	AR	(Rautenstrauch et al., 1977; Wiedemann, 1979)
FBN1 (*134797)	Fibrillin-1	Marfan Lipodystrophy Syndrome / Partial	MFLS (#616914)	Severe loss of sWAT.	AD	(Horn & Robinson, 2011; Takenouchi et al., 2013)
RECQL2 (*604611)	DNA helicase, RECQ protein-like 2	Werner Syndrome / Partial	WRN (#277700)	Loss of sWAT.	AR	(Werner, 1985; Huang et al., 2006)
RECQL3 (*604610)	DNA helicase, RECQ protein-like 3	Bloom Syndrome / Partial	BLM (#210900)	Loss of sWAT.	AR	(Bloom, 1954; Diaz et al., 2006)
LMNA (*150330)	Lamin-A/C	Type A Mandibuloacral Dysplasia with Lipodystrophy / Partial	MADA (#248370)	Partial loss of sWAT.	AR	(Young et al., 1971)
ZMPSTE24 (*606480)	Zinc metalloproteinase STE24 homolog	Type B Mandibuloacral Dysplasia with Lipodystrophy / Generalized	MADB (#608612)	Generalized loss of sWAT.	AR	(Agarwal et al., 2003a)
BANF1 (*603811)	Barrier-to-autointegration factor	Néstor-Guillermo Progeria Syndrome / Generalized	NGPS (#614008)	Generalized loss of sWAT.	AR	(Puente et al., 2011)
SPRTN (*616082)	DNA-Dependent Metalloprotease Spartan	Ruijs-Aalfs Syndrome / Generalized	RJALS (#616200)	Loss of sWAT.	AR	(Ruijs et al., 2003; Lessel et al., 2014)
ERCC8 (*609412)	Excision repair cross-complementing, group 8	Type A Cockayne Syndrome / Generalized	CSA (#216400)	Progressive loss of sWAT.	AR	(Nance & Berry, 1992; Brace et al., 2013; Brace et al., 2016)
ERCC6 (*609413)	Excision repair cross-complementing, group 6	Type B Cockayne Syndrome / Generalized	CSB (#133540)	Generalized sWAT loss.	AR	(Nance & Berry, 1992; Van Der Pluijm et al., 2007)
ERCC4 (*133520)	Excision repair cross-complementing, group 4	Xeroderma Pigmentosum Complementation Group F	XPF (#278760)	Generalized sWAT loss.	AR	(Niedernhofer et al., 2006)
LMNA (*150330)	Lamin-A/C	Hutchinson-Gilford Progeria Syndrome / Generalized	HGPS (#176670)	sWAT loss.	AD	(Hutchinson, 1886; Goldman et al., 2004)
CAV1 (*601047)	Caveolin-1	Severe premature aging and lipodystrophy	-	Generalized sWAT loss.	AR	(Schrauwen et al., 2015; Garg et al., 2015)
POLD1 (*174761)	DNA polymerase delta 1	Mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome.	MDPL (#615381)	Prominent loss of sWAT.	AD	(Shastry et al., 2010; Weedon et al., 2013)
Classical inherited lipodystrophies due to pathogenic variants mainly in genes associated with adipogenesis.
LMNA (*150330)	Lamin-A/C	Type 2 Familial Partial Lipodystrophy / Partial	FPLD2 (#151660)	Partial loss of sWAT.	AD	(Caron et al., 2007)
PPARG (*601487)	PPARγ	Type 3 Familial Partial Lipodystrophy / Partial	FPLD3 (#604367)	Partial loss of sWAT.	AD	(Agarwal and Garg, 2002; Hegele et al., 2002)
PLIN1 (*170290)	Perilipin-1	Type 4 Familial Partial Lipodystrophy / Partial	FPLD4 (#613877)	Partial loss of sWAT.	AD	(Gandotra et al., 2011)
CIDEC (*612120)	Cell Death Inducing DFFA like Effector C	Type 5 Familial Partial Lipodystrophy / Partial	FPLD5 (#615238)	Partial loss of sWAT.	AR	(Rubio-Cabezas et al., 2009)
Classical inherited lipodystrophies due to pathogenic variants mainly in genes associated with adipogenesis.
LIPE (*151750)	Hormone-sensitive lipase (HSL)	Type 6 Familial Partial Lipodystrophy / Partial	FPLD6 (#615980)	Partial loss of sWAT.	AR	(Albert et al., 2014; Zolotov et al., 2017)
CAV1 (*601047)	Caveolin-1	Type 7 Familial Partial Lipodystrophy / Partial	FPLD7 (#606721)	Partial loss of sWAT.	AD	(Cao et al., 2008)
MFN2 (*608507)	Mitofusin 2	Multiple Symmetric Lipomatosis / Partial	MSL (#151800)	Partial loss of sWAT.	AR	(Capel et al., 2018)
AGPAT2 (*603100)	1-AGPAT 2	Type 1 Berardinelli-Seip Congenital Lipodystrophy / Generalized	CGL1 (#608594)	Generalized loss of sWAT.	AR	(Agarwal et al., 2002)
BSCL2 (*606158)	Seipin	Type 2 Berardinelli-Seip Congenital Lipodystrophy / Generalized	CGL2 (#269700	Generalized loss of sWAT.	AR	(Magré et al., 2001)
CAV1 (*601047)	Caveolin-1	Type 3 Berardinelli-Seip Congenital Lipodystrophy / Generalized	CGL3 (#612526)	Generalized loss of sWAT.	AR	(Kim et al., 2008)
CAVIN1 (*603198)	Cavin-1	Type 4 Berardinelli-Seip Congenital Lipodystrophy / Generalized	CGL4 (#613327)	Generalized loss of sWAT.	AR	(Hayashi et al., 2009; Rajab et al., 2010)

• OMIM: Online Mendelian Inheritance in Man. AR: Autosomal recessive. AD: Autosomal dominant.

Congenital generalized lipodystrophies - CGLs

The lack of sWAT in CGL causes a decrease in leptin levels and alters food intake, intensifying the appetite (Badman & Flier, 2007; Rodríguez et al., 2016). The blood circulating lipids result in hypertriglyceridemia (HTG), and their accumulation in ectopic sites, such as in the liver and skeletal muscle, can result in hepatic steatosis and weakness of respiratory muscle strength, respectively (Debray et al., 2013; Dantas De Medeiros et al., 2018; Araújo de Melo Campos et al., 2021). Severe IR causes hypertension, HTG, and difficulty in controlling diabetes. Liver fat deposition can result in cirrhosis. These comorbidities could explain the severity of CGL and its early mortality (Lima et al., 2018b).

The most common pathogenic variants associated with CGLs are in AGPAT2 and BSCL2 genes, related to types 1 and 2 (CGL1 and CGL2), respectively (Magré et al., 2001; Agarwal et al., 2002; Craveiro Sarmento et al., 2019). Although CGL1 and CGL2 have similar metabolic abnormalities, the sWAT loss is less severe in CGL1 individuals, which have more mechanical sWAT, while CGL2 individuals display a significant reduction of both metabolically active and mechanic sWAT (Garg et al., 1992; Agarwal et al., 2003b; Simha and Garg, 2003). Regarding the AGPAT2 gene, it codifies to the 1-acylglycerol-3-phosphate o-acyltransferase (1-AGPAT 2) enzyme, which is associated with the synthesis of triacylglycerol (TG) and phospholipids in the ER (Agarwal and Garg, 2003). Recessive pathogenic variants in the BSCL2 gene, which codifies to the ER membrane-localized seipin, are the genetic cause of CGL2 (Magré et al., 2001). This protein acts to regulate the TG transport from the ER to lipid droplets (LDs) (Salo et al., 2019), converting nascent to mature LDs (Wang et al., 2016) and regulating ER-LDs contacts and cargo delivery (Salo et al., 2016). Seipin has essential functions related to adipose tissue homeostasis, such as coordinating 1-AGPAT2 function (Sim et al., 2020) and controlling Ca²⁺ (calcium) import and adipocyte metabolism at ER-mitochondria sites (Combot et al., 2022).

Type 3 CGL (CGL3) occurs due to homozygous pathogenic variants in the CAV1 gene that codifies to caveolin-1 (Kim et al., 2008), whereas type 4 CGL (CGL4) occurs due to pathogenic variants in the CAVIN1 gene, which codifies to the cavin-1 protein (Hayashi et al., 2009; Rajab et al., 2010). Both cavin-1 and caveolin-1 are present in caveolae, which are cave-like structures located at the plasma membrane in most cells, mainly adipocytes. Caveolae are involved in cellular processes, such as cell metabolism, cholesterol homeostasis, cell proliferation, and senescence (Parton, 2018). However, the number of pathogenic variants in both genes is scarce relative to CGL1 and CGL2. Table 1 contains a summary of the the molecular basis and sWAT physiology of CGL syndromes.

At the morphological level, CGL subjects present a typical phenotype, revealing acromegalic facies, prominent musculature, prognathism, phlebomegaly (prominent veins), umbilical protrusion, acanthosis nigricans, acrochordons, hirsutism, bone cysts, and others (Garg, 2000; Maldergem et al., 2002; Agarwal et al., 2003b; Garg and Agarwal, 2009; Vigouroux et al., 2011; Lima et al., 2016; Lima et al., 2017; Lima et al., 2018a). At metabolic and physiological levels, CGL subjects present dyslipidemia, hyperinsulinemia, IR, DM, low levels of leptin and adiponectin, decreased levels of high-density lipoprotein cholesterol (HDL-c), hepatosplenomegaly, and hypertrophic cardiomyopathy (Faria et al., 2009; Lima et al., 2016; de Azevedo Medeiros et al., 2017; Ponte et al., 2018; Dantas De Medeiros et al., 2018).

Familiar partial lipodystrophies - FPLDs

Concerning the FPLDs, eight subtypes were described, and the primary molecular causes of these heterogeneous diseases are genes related to the nuclear envelope and adipocyte homeostasis, such as LMNA and PPARγ (Patni and Garg, 2015; Araújo-Vilar and Santini, 2019; Fernández-Pombo et al., 2021). Type 1 FPLD (FPLD1, also named Köbberling syndrome) is probably a multigenic form of lipodystrophy (Patni and Garg, 2015; Araújo-Vilar and Santini, 2019). The most frequent FPLD is the Dunnigan syndrome, also referred to as type 2 FPLD (FPLD2), which occurs due to pathogenic variants in the LMNA gene. This gene encodes lamin-A and lamin-C (besides lamins CΔ10 and C2) which play a significant function in maintaining the stability of the cellular nucleus by physically supporting nuclear envelope components (Gonzalo et al., 2017). Over 400 pathogenic variants were described in the LMNA gene. In addition to FPLD2, they are related to more than a dozen degenerative diseases, such as neuropathies, muscular dystrophies, and premature aging (Broers et al., 2006; Bertrand et al., 2011; Gonzalo and Kreienkamp, 2015). Recent reviews discussed the association between LMNA variants and several diseases (Ho and Hegele, 2019; Lazarte and Hegele 2021). However, how different LMNA pathogenic variants result in a plethora of diseases has yet to be unraveled.

FPLD2 phenotype was initially described in 1974 by Dunnigan and first associated with the LMNA gene in 1998 by Peters et al. (Dunnigan et al., 1974; Peters et al., 1998). This disease is characterized by loss of sWAT in the extremities and trunk, sparing the face and neck at puberty. Lamins A/C, encoded by the LMNA gene, are nuclear proteins, and specific pathogenic variants may lead to nuclear function disruption, resulting in premature adipocyte death (Garg, 2011). FPLD2 subjects show loss of sWAT mainly in the axial skeleton, such as in limbs, trunk, hips, and gluteus, but not in the appendicular skeleton (Garg et al., 2001; Chan et al., 2016). FPLD2 metabolic disturbances include HTG, low HDL-c levels, IR, hepatic steatosis, pancreatitis, and a high probability of developing cardiovascular diseases (Araújo-Vilar and Santini, 2019; Lazarte et al., 2021).

Type 3 (FPLD3) is caused by pathogenic variants in the PPARγ gene. In 1999, three subjects were reported with severe IR harboring two different heterozygous pathogenic variants in the ligand-binding domain of peroxisome proliferator-activated receptor type γ (PPARγ) (Barroso et al., 1999). Later, these variants were associated with FPLD3 (Savage et al., 2003). As PPARγ is a critical transcription factor for adipogenesis, its dominant pathogenic variants may impair adipocyte differentiation (Garg, 2011). This type is characterized by loss of sWAT in the extremities, especially in distal regions (Araújo-Vilar and Santini 2019).

Type 4 FPLD (FPLD4) was described and associated with two distinct heterozygous frameshift pathogenic variants in the PLIN1 gene (Gandotra et al., 2011). The PLIN1 gene encodes perilipin-1, an integral component of LDs, playing an essential role in lipid storage and hormone-regulated lipolysis (Garg, 2011). In this type, lipoatrophy is mainly evident in the gluteal regions and lower limbs, although the loss of subcutaneous fat has also been observed in the trunk and upper limbs.

Type 5 FPLD (FPLD5) is caused by a homozygous truncating pathogenic variant in the CIDEC gene that was first reported in 2009 (Rubio-Cabezas et al., 2009). The clinical hallmarks are loss of sWAT in the lower limbs, prominent muscle mass, IR, diabetes, and decreased LD size in adipocytes. The CIDEC gene encodes the Cell Death Inducing DFFA Like Effector C (CIDEC) protein that is associated with LDs, inhibiting lipolysis and promoting the formation of unilocular LDs in adipocytes (Garg, 2011).

Type 6 FPLD (FPLD6) is triggered by a homozygous pathogenic variant in the LIPE gene. The first to describe this disease and its association with this gene were Albert et al. (2014). The main clinical manifestations of this disease are progressive loss of sWAT in the legs that correlate with abnormal fat distribution, including fat accumulation in the neck, face, axilla, shoulders, back, abdomen, and pubic region. Furthermore, in some cases, myopathy, diabetes, HTG, low HDL-c, and hepatic steatosis may be observed (Zolotov et al., 2017).

Pathogenic variants in the CAV1 gene, first related to CGL3, were also found in type 7 FPLD (FPLD7) individuals (Cao et al., 2008). However, heterozygous pathogenic variants in this gene are responsible for causing FPLD7 (Cao et al., 2008). This disease is characterized by loss of sWAT in different regions of the body, accompanied by metabolic complications such as IR, lipid abnormalities, and in some cases, cataracts and muscle spasticity (Garg et al., 2015). More studies are required to unravel the role of distinct CAV1 pathogenic variants in different types of congenital lipodystrophies, such as CGL3, FPLD7, and the neonatal onset of generalized lipodystrophy (Cao et al., 2008; Schrauwen et al., 2015; Garg et al., 2015). Table 1 summarizes the molecular basis and sWAT physiology of FPLD syndromes.

Progeroid disorders

Monogenic, premature aging diseases are heterogeneous syndromes and present variable severity and overlapping phenotypes, making it difficult for the correct clinical diagnosis (Carrero et al., 2016). Molecular investigations are essential for deciphering the genetic causes of progeroid overlapping diseases. The hallmarks of progeroid syndromes include increased DNA damage accumulation, defective DNA repair, telomere dysfunction, aberrant nuclear architecture and chromatin structure, impaired cell cycle, senescence, disrupted epigenetics regulation, and lack of sWAT (Agarwal and Garg, 2006; Carrero et al., 2016; Niedernhofer et al., 2018).

Cockayne Syndrome

Cockayne Syndrome (CS) is a progressive rare autosomal recessive disorder, first described through the clinical study of two patients (Cockayne, 1936). This disease results in postnatal growth failure, and progressive neurologic dysfunction primarily due to demyelination, and photosensitivity (Nance and Berry, 1992).

CS may manifest as delayed psychomotor development, behavioral and intellectual deterioration, microcephaly, increased or decreased muscle tone and reflexes, gait ataxia, tremor, incoordination, dysarthric speech, pigmentary degeneration of the retina, cataracts, optic atrophy or optic disk pallor, sensorineural hearing loss, dental complications, kidney complications, hyperinsulinemia or abnormal glucose tolerance, elevated serum cholesterol or lipoprotein levels, and very low levels of HDL-c (Nance and Berry, 1992).

The aged appearance may come from the expression of thin hair, diminished subcutaneous tissue, scaly skin, erythematous dermatitis on the dorsum of the hands and wrists, on the legs, and on the face and ears, worsened after exposure to the sun, small faces with sunken eyes and prominent superior maxillae (Cockayne, 1936).

Xeroderma Pigmentosum

Xeroderma Pigmentosum (XP) was first documented in 1884 when three affected patients were clinically studied, presenting freckle-like pigment spots which appeared simultaneously upon the face, neck, back of forearms, hands, upper arms, and legs below the knees (Crocker, 1884). Later, other studies showed that such cutaneous symptoms had a median age of onset of between one and two years, and about forty-five percent of the patients had basal cell carcinoma or squamous cell carcinoma of the skin. Many of them also presented neurologic abnormalities, including progressive mental deterioration, hyporeflexia or areflexia, and progressive deafness, associated with dwarfism and immature sexual development (Cleaver, 1968; Kraemer et al., 1987). Next, James Cleaver discovered that fibroblasts obtained from XP patients displayed defective DNA repair after ultraviolet UV exposure (Cleaver, 1968).

This condition has at least eight genetic groups, types A to G and a variant, which were identified through genetic complementation analysis (Tanaka, 1993). Cells from patients with the hereditary disease XP were expected to carry pathogenic variants in DNA repair genes. Their expression was either absent or much reduced compared to normal fibroblasts (Cleaver, 1968). This disorder presents over a 1,000-fold increased risk of skin cancer and a 10-fold increased risk of other tumors, along with progeroid symptoms. These symptoms were found in an XP patient, including an aged appearance, weight loss, epidermal atrophy, visual and hearing loss, ataxia, cerebral atrophy, hypertension, liver dysfunction, anemia, osteopenia, kyphosis, sarcopenia, and renal insufficiency (Niedernhofer et al., 2006).

Néstor-Guillermo Progeria Syndrome

Néstor-Guillermo Progeria Syndrome (NGPS) is a chronic progeroid disease characterized by aging phenotypes, including growth retardation, thin limbs, and loss of sWAT. NGPS is caused by a homozygous pathogenic variant in the BANF1 gene (c.34G>C; p.A12T), that encodes BANF1/BAF1 (barrier-to-autointegration factor 1) (Puente et al., 2011). Two unrelated Spanish families were clinically investigated by Puente et al. (2011). Both had the c.34G>A [p.Ala12Thr] pathogenic variant in the BANF1 gene. Skin fibroblasts from these patients exhibited deficient BANF1 levels and profound nuclear abnormalities, including blebs and aberrations. Concurrently, transfected mutant fibroblasts with an expression vector encoding an EGFP-BAF fusion protein, and confocal microscopy analysis, revealed that ectopic expression of EGFP-BAF in these progeroid fibroblasts rescued the nuclear abnormalities, confirming the causal role of the BAF p.Ala12Thr pathogenic variant (Puente et al., 2011). Later in the same year, Cabanillas et al. (2011) published a detailed clinical report of the two affected patients from the two unrelated families previously described.

Affected patients showed partial phenocopy of Hutchinson Gilford Progeria Syndrome (HGPS) and Mandibuloacral dysplasia (MAD) but without cardiovascular alterations and metabolic abnormalities. They presented a collection of clinical outcomes that suggested a new progeroid syndrome. Such manifestations included: very severe osteolysis with intense bone resorption, a long lifespan relative to HGPS and MAD, presence of eyebrows and eyelashes, and persistence of scalp hair. They also observed a generalized loss of sWAT over the limbs and trophic facial subcutaneous fat pad, abdomen, neck, and head, and dry and atrophic skin with small light-brown spots over the thorax, scalp, and limbs. Low levels of 25-OH-vitamin D and leptin were also seen (Cabanillas et al., 2011; Puente et al., 2011).

Werner and Bloom Syndromes

Werner (WS) and Bloom (BS) syndromes are rare recessive autosomal diseases characterized by clinical features of premature aging that are caused by loss-of-function pathogenic variants in the WRN (RECQL2) and BLM (RECQL3) genes, respectively (Ellis and German, 1996; Yu et al., 1996; Hickson, 2003). WRN (WRN RecQ Like Helicase) and BLM (BLM RecQ Like Helicase) are ubiquitously expressed RECQ helicases that play major roles in a wide variety of DNA repair processes required for genomic integrity maintenance. WS was first described by Otto Werner in 1904, who presented the clinical WS phenotype as a “caricature of aging” (Werner 1985). WS patients exhibit metabolic complications including IR, DM, dyslipidemia, and fatty liver, as well as cataracts, cancer, and premature aging. Atherosclerosis is more frequent from the third decade onwards. At a molecular level, WS cells display a high rate of spontaneous mutations and karyotypic abnormalities, in addition to aberrant recombination, telomere defects, and hypersensitivity to DNA damage and/or cellular stress (Turaga et al., 2009).

WS patients develop normally until the second decade of life, and the first clinical sign is the lack of peak pubertal growth. Between 20 and 30 years of age, patients begin to suffer from skin atrophy, gray hair, and hair loss. Soft tissue calcification is a feature often associated with ulcerations around the ankles (and occasionally elbows) that eventually may require lower limb amputation (Takemoto et al., 2013). Other complications include type 2 DM, osteoporosis, bilateral ocular cataract, premature and severe forms of arteriosclerosis, peripheral neuropathy, and multiple cancers mainly perceived in middle age (Lauper et al., 2013). These patients generally present a median age of death around 54 years, typically due to cancer or myocardial infarction (Goto, 1997; Goto et al., 2013; Martin et al., 2021). WRN protein has exonuclease and helicase activities that are important for genome integrity maintenance. This protein interacts physically and functionally with enzymes that play central roles in DNA replication and repair. It is remarkable that replication and recombination functions also appear to underlie the telomeres maintenance by RecQ helicases (Turaga et al., 2009).

BS, also referred to as congenital telangiectatic erythema, was first described in 1954 (Bloom, 1954). This progeroid syndrome is caused by pathogenic variants in the BLM gene that results in errors in the DNA replication process, and a pronounced number of chromosomal breaks and rearrangements, leading to the symptoms and clinical feature of BS (Bloom, 1954; Hickson, 2003). BS patients generally demonstrate postnatal growth retardation, facial butterfly rash, often after exposure to sunlight, defective cellular and humoral immunity, and an increased risk of cancer, besides a high prevalence of DM, dyslipidemia, and hepatic steatosis. Both WS and BS syndromes show metabolically phenocopies of lipodystrophy (reduction in sWAT) and obesity (Epstein et al., 1966; Diaz et al., 2006; Goh et al., 2020).

Hutchinson Gilford Progeria Syndrome

HGPS is considered one of the most severe laminopathies, being included in the group of premature aging degenerative diseases. Patients live for an average of just 14.6 years, dying primarily due to myocardial infarction or strokes (Gordon et al., 2014). HGPS was first described in 1886 by the British physician Jonathan Hutchinson and, later, by Hastings Gilford in 1904 (Hutchinson, 1886; McKusick, 2005). The main clinical manifestations of HGPS patients are sWAT loss, alopecia, Ca²⁺ dysfunction, vascular stiffening, delayed dentition, heart infarction, and progressive arteriosclerosis (Goldman et al., 2004; Prokocimer et al., 2013). Molecularly, HGPS patient cells have nuclear shape abnormalities, telomere shortening, genomic instability, alterations in epigenetic regulation and gene expression, mitochondrial dysfunction, and premature senescence.

HGPS occurs due to the heterozygous silent pathogenic variant c.G608G in the LMNA gene (Eriksson et al., 2003; De Sandre-Giovannoli et al., 2003). LMNA encodes the prelamin-A, which undergoes post-translational processing, leading to transient production of different intermediates, including farnesylated prelamin-A and carboxymethylated prelamin-A (Lattanzi et al., 2014). The zinc metalloproteinase STE24 homolog (ZMPSTE24) cleaves the prelamin-A in two independent steps: the first is the cleavage of the last three amino acids in the C-terminal region of farnesylated prelamin-A. This cleavage can also be performed by Ras converting CAAX endopeptidase 1 (RCE1). The second cleavage of farnesylated and carboxymethylated prelamin-A occurs at the leucine 647 (L647) and results in the removal of the last fifteen amino acids, producing the mature, unfarnesylated lamin-A (Lattanzi et al., 2014). The pathogenic variant c.G608G in the LMNA gene leads to the loss of the recognition site for the second cleavage of the farnesylated prelamin-A by ZMPSTE24 (Eriksson et al., 2003; De Sandre-Giovannoli et al., 2003). This change results in the accumulation of a permanently farnesylated and carboxymethylated dominant protein, referred to as progerin, disrupting the nuclear envelope (Broers et al., 2006; Bertrand et al., 2011; Bidault et al., 2020; Saxena and Kumar, 2020). Furthermore, the accumulation of farnesylated prelamin-A is related to nuclear enlargement, heterochromatin loss, euchromatin dispersion, and increased ROS production (Richards et al., 2011).

Type A Mandibuloacral Dysplasia with Lipodystrophy

Type A Mandibuloacral Dysplasia with Lipodystrophy (MADA) is a rare autosomal recessive disease in which the patients commonly present slow and progressive osteolysis of the mandible, terminal phalanges, and clavicles, resulting in mandibular hypoplasia, dental crowding, and clavicular resorption, as well as skin abnormalities, acanthosis nigricans, and partial lipodystrophy. However, there is an absence of neurodegeneration. This condition is associated with accelerated aging and is usually identified after 4 or 5 years after birth (Novelli et al., 2002). MADA patients express a partial lipodystrophy pattern of body fat distribution with degeneration of sWAT in the torso and limbs and accumulation in the face, neck, and trunks (Novelli et al., 2002). This syndrome may be associated with clinical features of metabolic syndromes, including IR, which was evidenced in the clinical study of three patients with MAD (Freidenberg et al., 1992), impaired glucose tolerance, DM, and lack of breast development with regular or irregular menstrual periods in female patients (Cenni et al., 2018). This disorder is caused by the accumulation of prelamin-A in MADA cells, leading to the restraint of cellular differentiation due to the impaired import of transcription factors required for adipogenic gene activation or stress response (Cenni et al., 2018).

MAD was first reported by Young et al. (1971). Since then, other authors studied different cases of MAD in patients, such as Zina et al. (1981), Pallotta and Morgese (1984), and Tenconi et al. (1986), although the cause was still unknown. The official association between MADA and the LMNA gene was published in 2002, through the clinical and genetic investigation of five consanguineous Italian families, whose skin fibroblasts showed abnormal lamin nuclei (Novelli et al., 2002).

Pathogenic variants in the LMNA gene, such as p.Arg471Cys, p.Arg527Cys, p.Arg527Leu, p.Arg527His, p.Ala529THR, p.Ala529Val, and p.Met540Ile (Marcelot et al., 2020), cause the accumulation of prelamin A (non farnesylated) to toxic levels, along with the mutated prelamin A (farnesylated), affecting the whole organization of the nuclear envelope. The most common pathogenic variant responsible for the MADA phenotype is the homozygous missense substitution of c.1580G > A mapping in the exon 9 of the LMNA gene, resulting in the p.Arg527His mutated protein. These variants in the LMNA gene cause loss of interaction between lamin-A and other proteins, impacting stress recovery mechanisms in MADA cells, which means that repeated stress stimuli and failure to properly manage this condition led to senescence. These cells show nuclear dysmorphism, loss of peripheral heterochromatin, and nuclear lamina thickening (Cenni et al., 2018).

Type B Mandibuloacral Dysplasia with Lipodystrophy

Type B Mandibuloacral Dysplasia with Lipodystrophy (MADB) is a rare autosomal recessive premature aging disease (Agarwal et al., 2003a). MADB is characterized by IR, metabolic comorbidities, atrophic skin, brittle hair, generalized loss of sWAT, skeletal abnormalities such as mandibular and clavicular hypoplasia, and acro-osteolysis of the distal phalanges (Hitzert et al., 2019). Although MADB and MADA have many similarities, MADB individuals develop early skeletal abnormalities (Agarwal et al., 2003a). ZMPSTE24 pathogenic variants are responsible for many different diseases, depending on the degree of prelamin-A processing impairment (Shackleton et al., 2005). MADB is caused by compound heterozygous or homozygous pathogenic variants in the ZMPSTE24 gene, resulting in reduced activity of the metalloprotease ZMPSTE24. Compound heterozygous variants in the ZMPSTE24 gene, such as p.Phe361fsX379/p.Trp340Arg (Agarwal et al., 2003a), p.Phe361fsX379/p.Asn265Ser (Shackleton et al., 2005; Agarwal et al., 2006), p.Gln41X/p.Pro248Leu (Miyoshi et al., 2008), p.Tyr70fs/p.Asn265Ser (Cunningham et al., 2010), and p.Pro248Leu/p.Trp450X (Ahmad et al., 2010), as well as the homozygous variants p.Leu94Pro (Yaou et al., 2011) and p.Tyr399Cys (Haye et al., 2016), can partially or totally affect the functions of the metalloprotease ZMPSTE24, resulting in the accumulation of farnesylated prelamin-A and progressive loss of sWAT. Zmpste24 ^-/- mice also displayed almost completed loss of sWAT due to the toxic accumulation of farnesylated prelamin-A (Bergo et al., 2002; Pendás et al., 2002).

Wiedemann-Rautenstrauch Syndrome

The POLR3A gene encodes the largest subunit of RNA polymerase III (Pol III), forming the catalytic core with POLR3B. Pol III is responsible for the transcription of different kinds of non-protein-coding RNAs, which regulate transcription, RNA processing, and translation (Sepehri and Hernandez 1997; Werner et al., 2009; Wu et al., 2021). This protein also acts in the proper function of the nucleolus, including ribosome assembly by enhancing 5S rRNA synthesis and protein translation, determining the metabolic state of the cell (Tiku and Antebi 2018; Báez-Becerra et al., 2020).

Wiedemann-Rautenstrauch Syndrome (WRS) was first studied in 1977 (Rautenstrauch et al., 1977) and in 1979 (Wiedemann, 1979), both studies through clinical reports of patients with a progeroid syndrome, utilizing their lymphocytes and cultured skin fibroblasts. The relation between WRS and pathogenic variants in the POLR3A gene was confirmed by investigating DNA and RNA samples and fibroblast cultures of two affected Bulgarian families (Azmanov et al., 2016), showing that the POLR3A gene is the primary locus for the WRS phenotype. Since then, studies have presented POLR3A biallelic variants that alter splicing and/or truncate translation and are associated with WRS, such as c.1909þ18G>A and c.2617C>T (Jay et al., 2016), c.3337-5T>A, c.3337-11T>C, c.490+1G>A, c.2005C>T, c.760C>T, c.1572+1G>A, c.2617-1G>A, c.3G>T and c.*18C>T (Wambach et al., 2018), all found in clinical and genetic analysis of WRS patients. Accordingly, these POLR3A alterations are the cause of the WRS progeroid disease.

WRS is sporadic and heterogeneous, characterized by intrauterine growth restriction (IUGR), poor postnatal weight gain, characteristic facial features, pseudohydrocephalus, generalized lipodystrophy, with an almost complete lack of subcutaneous fat and possible paradoxical caudal fat accumulation, premature alopecia, neonatal teeth, and teeth abnormalities (Rautenstrauch et al., 1977; Wiedemann, 1979). The progressive generalized lipodystrophy manifests with local fatty tissue accumulations, and cachectic appearance (Paolacci et al., 2017; Lessel and Kubisch, 2019).

Ruijs-Aalfs Syndrome

The SPRTN gene encodes to Spartan protein, a DNA-dependent metalloprotease associated with the replication machinery that repairs DNA-protein crosslinks (DPCs) through the SprT protease domain (Maskey et al., 2014, 2017). DPCs derive from proteins covalently and irreversibly bound to DNA, such as Topoisomerase 1 (Top1), and the SPRTN (SprT-Like N-Terminal Domain) proteolytic activity, which upon DNA and ubiquitin-binding and promotes cleavage of DPC substrates and itself (Lopez-Mosqueda et al., 2016; Li et al., 2019). Spartan malfunction, as a consequence of pathogenic variants such as c.721delA and c.350A>G (Lessel et al., 2014), is responsible for replication stress, which has been suggested to cause DSBs, translocation mosaicism, and genomic instability. Thus, pathogenic variants in the SPRTN gene have been linked to cancer and aging, more specifically to the Ruijs-Aalfs syndrome (RJALS), an autosomal recessive disorder firstly described by Ruijs et al. (2003). RJALS individuals display genome instability, short stature, cataract, progeria, low body weight, micrognathia, triangular face, muscular atrophy, lipodystrophy, and early-onset hepatocellular carcinoma (Ruijs et al., 2003; Lessel et al., 2014).

The first association between SPRTN pathogenic variants, progeroid syndromes, and liver tumors was made in 2014, using Sprtn hypomorphic mice (Maskey et al., 2014) and in primary skin fibroblasts, liver tumor biopsies, and lymphoblastoid cells (LCLs) from three progeroid patients, as well as in U2OS, and HEK293T cell lines (Lessel et al., 2014). The pathogenic variants in the SPRTN gene, such as SPRTN-∆C and SPRTN-Y117C, and defects in DPC repair were shown in 2016 (Lopez-Mosqueda et al., 2016; Stingele et al., 2016; Vaz et al., 2016).

Genes related to DNA repair and genomic stability resulting in progeroid diseases with lipodystrophy

In the last years, a plethora of molecular findings unraveling the link between DNA damage/repair and adipogenesis in human and animal models has emerged. In this section, we will highlight the main findings concerning the role of genes related to DNA repair and genomic stability in progeroid syndromes with lipodystrophy. Table 2 summarizes the main findings of this section.

Table 2 -
The main progeroid and classical inherited lipodystrophies associated with changes in DNA repair and genome stability.

Gene	Protein	Cell model	Changes in redox homeostasis and DNA repair	Adipose tissue and metabolic commitments	Reference
LMNA	Lamin-A/C	Fibroblasts from FPLD2 subjects harboring the pathogenic variants in the LMNA genes (p.D47Y, p.L92F, p.L387V, p. R399H, p.L421P, and p. R482W)	Oxidative stress, mitochondrial dysfunction, cell cycle arrest, and premature senescence.	Partial loss of sWAT.	(Caron et al., 2007)
LMNA	Lamin-A/C	Smooth Muscle Cells (SMCs) and fibroblasts from HGPS individuals carrying the pathogenic variant p.G608G.	PARP-1 suppression. Frequent DSBs, persistent activation of ATM and ATR. Higher levels of p-Chk-1, p-Chk-2, and p-p53. Mitochondrial dysfunction and NFE2L2 sequestration by progerin.	-	(Liu et al., 2006; Zhang et al., 2014; Kubben et al., 2016)
LMNA	Lamin-A/C	Fibroblasts from MADA individuals harboring the pathogenic variant p.R527H in the LMNA gene.	High levels of chromosome aberrations. Increased phosphorylated ATM-S1981 foci and γ-H2AX, and p53 after IR treatment.	-	(Di Masi et al., 2008)
LMNA and ZMPSTE24	Lamin-A/C and Zinc metalloproteinase STE24 homolog	Zmpste24-/- MEFs and HGPS fibroblasts carrying the pathogenic variant p.G608G.	High 53BP1 foci and increased protein levels of γH2AX and p-chk1. High sensibilization of Zmpste24 -/- MEFs to DNA-damage agents. Delayed γH2AX/53BP1 co-localization. Higher DNA damage levels and decreased Rad51 foci formation.	-	(Liu et al., 2005)
ERCC8 and XPA	CSA and XPA	CX (Csa -/- /Xpa-/- ) mice with similar aspects of human progeria.	Increase in FAO/OXPHOS, decline of NAD+ and ATP levels, and increased levels of pAMPK due to PARP-1 activity.	Progressive loss of sWAT, low levels of TGs, and glucose. Decline in mature adipocyte size without crown-like (CL) structures, decreased sWAT and perigonadal WAT. Low levels of glucose, insulin, HOMA-IR, TGs, and leptin levels.	(Brace et al., 2013; Brace et al., 2016)
ERCC6 and XPA	CSB and XPA	Csbm/m /Xpa-/- mice mimic the human progeroid CS syndrome.	Upregulation of genes associated with fatty acids synthesis and genes encoding antioxidant enzymes in the liver. Downregulation of genes involved in glycolysis, TCA, and OXPHOS.	sWAT loss and upregulation of Lepr and Pparg. Increased levels of TGs and glycogen accumulation. Low levels of glucose and IGF.	(Van Der Pluijm et al., 2007)
ERCC6	CSB and XPC	Csbm/m /Xpc-/- mice mimic the human progeroid CS syndrome.	-	sWAT loss.	(Van Der Pluijm et al., 2007)
ERCC1 and ERCC4	Ercc1 and XPF	Ercc1-/- mice and XFE (XPF-ERCC1) fibroblasts from a subject harboring c.458 G>C in the ERCC4 gene.	Sensitivity to oxidative stress. Upregulation of genes associated with fatty acids synthesis and genes encoding antioxidant enzymes in the liver.	sWAT loss and upregulation of Lepr and Pparg. Low levels of glucose, insulin, and IGF.	(Niedernhofer et al., 2006)
ERCC1	ERCC1	Ercc1-/- fat depots from mice	Persistent DNA damage.	sWAT loss.	(Karakasilioti et al., 2013)
BANF1	Barrier-to-autointegration factor	Skin fibroblasts from NGPS subjects harboring c.34 G>A (p.A12T) in the BANF1 gene.	Defective PARP-1 activity and disrupted repair of oxidized DNA lesions.	Generalized lipodystrophy.	(Bolderson et al., 2019)
RECQL2	DNA helicase, RECQ protein-like 2	WRN-/- human pluripotent stem cells (hPSCs) that were differentiated in adipocyte precursors (APs)	Reduced cell proliferation, shorter telomeres, and senescence.	Attenuated differentiation of WRN -/- APs to mature adipocytes and low adiponectin secretion. Low expression levels of FABP4, CEBPA, GLUT4, and ADIPOQ mRNAs in WRN -/- APs.	(Goh et al., 2020)
RECQL3	DNA helicase, RECQ protein-like 3	BLM-/- human pluripotent stem cells (hPSCs) that were differentiated in adipocyte precursors	Reduced cell proliferation, shorter telomeres, and senescence.	Attenuated differentiation of BLM -/- APs to mature adipocytes. Low expression levels of FABP4, CEBPA, GLUT4, and ADIPOQ mRNAs in WRN -/- APs.	(Goh et al., 2020)
POLR3A	RNA Polymerase III, subunit A	WRS fibroblasts carrying the pathogenic variant c.3772_3773delCT in the POLR3A gene.	Senescent cells. Increased levels of γH2AX and p53.	-	(Báez-Becerra et al., 2020)
SPRTN	DNA-Dependent Metalloprotease Spartan	SPRTN-depleted U2OS cells, RJALS fibroblasts, Sprtn F/- MEFs, SPRTN-KO MEFs, and RJALS lymphoblastoid cells.	Increased accumulation of γH2AX and 53BP1 after CPT treatment in SPRTN-depleted U2OS cells transfected with the mutant p.Tyr117Cys or ∆C-TER SPRTN. Severe growth defect and increased levels of DSBs in patient fibroblasts. Increased numbers of 53BP1 nuclear bodies in Sprtn F/- MEFs. High sensitivity of lymphoblastoid cells derived from RJALS and SPRTN-KO MEFs to DPCs-inductor agents.	-	(Maskey et al., 2014; Lessel et al., 2014; Lopez-Mosqueda et al., 2016)
POLD1	DNA polymerase delta 1	Individuals with MDPL harboring the heterozygous single codon deletion c.1812-1814delCTC (p.Ser605del) in the POLD1 gene.	The catalytic subunit of POLD1 was affected, resulting in no detectable polymerase activity.	Progressive lack of sWAT in childhood, increased visceral adipose tissue (vWAT), and insulin resistance. Fibrosis in sWAT and high levels of genes from ECM, such as TGFB1 andFN1.	(Shastry et al., 2010; Weedon et al., 2013; Reinier et al., 2015; Okada et al., 2017; Sasaki et al., 2018; Wang et al., 2018; Yu et al., 2021)
POLD1	DNA polymerase delta 1	Individuals with MDPL harboring a heterozygous variant in the exonuclease domain of the POLD1 gene (p.Arg507Cys)	-	Lipoatrophy in almost all body, but not in mechanic WAT.	(Pelosini et al., 2014)
POLD1	DNA polymerase delta 1	Individuals with MDPL harboring heterozygous variants in the ZNF1 domain of the POLD1 gene (c.3199 G>A; p.Glu1067Lys and c.3209 T>A; p.Ile1070Asn).	-	Generalized loss of sWAT and progeroid features in a patient harboring p.Ile1070Asn but not in the patients harboring p.Glu1067Lys, which had IR, elevated CK levels, and proteinuria.	(Ajluni et al., 2017; Elouej et al., 2017)
POLD1	DNA polymerase delta 1	HDFs from MDPL individuals harboring the heterozygous single codon deletion c.1812-1814delCTC (p.Ser605del) in the POLD1 gene.	Nuclear envelope abnormalities, intranuclear accumulation of prelamin-A, high levels of micronuclei, cellular senescence, and growth decline. High levels of γH2AX foci after cisplatin-induced DSBs.	Diminished sWAT in limbs and increased AT in neck, abdomen, mesenteric regions, and retroperitoneal space. Progeroid features.	(Fiorillo et al., 2018; Murdocca et al., 2021)
BSCL2	Seipin	Leukocytes from CGL2 subjects harboring c.325dupA in the BSCL2 gene.	High levels of oxidative stress and mitochondrial DNA damage. Upregulation of NFE2L2, APEX1, OGG1, and α-OGG1.	Severe loss of sWAT, Low HDL-c, low adiponectin and leptin levels, high levels of triglycerides in plasma	(Craveiro Sarmento et al., 2020)
CAV1 and AGPAT2	Caveolin-1 and 1-AGPAT 2	Whole blood from a subject harboring the heterozygous pathogenic variants c.479_480delTT (p.Phe160X) in the CAV1 and c.51_52insGTC in the AGPAT2 gene.	Downregulation of Fanconi anemia pathway, tricarboxylic acid (TCA) cycle, and oxidative phosphorylation (OXPHOS). Downregulation of AGPAT2, RECQL4, and WRN genes. Upregulation of the ATM gene.	Severe loss of sWAT. High levels of triglycerides in infancy. Low levels of caveolin-1 protein.	(Schrauwen et al., 2015)

• OMIM: Online Mendelian Inheritance in Man.

The LMNA gene and FPLD2

The link between changes in redox homeostasis, cell cycle, and senescence was investigated in fibroblasts from FPLD2 subjects carrying the pathogenic variants p.D47Y, p.L92F, p.L387V, p.R399H, p.L421P, and p.R482W in the LMNA genes (Caron et al., 2007). These pathogenic variants result in prelamin-A accumulation, the precursor of lamin-A, which was associated with the occurrence of mitochondrial dysfunction and higher levels of cytoplasmic ROS. Disturbances in the cell cycle and premature senescence were also found (Caron et al., 2007). Oxidative stress, inflammation, senescence, and calcification were also found in vascular smooth muscle cells (VSMCs) from FPLD2 subjects harboring R482W, D47Y, and R133L LMNA pathogenic variants (Afonso et al., 2016). This study only investigated DSBs accumulation by evaluating the amount of γH2AX foci. Unrepaired DSBs accumulation was also verified in human coronary artery endothelial cells (HCAECs) transduced with adenoviral vectors containing Flag-tagged p.R482W prelamin-A cDNA It was also verified that pravastatin treatment decreased the levels of γH2AX foci (Bidault et al., 2013).

Further, prelamin-A accumulation was directly associated with accumulation of DSBs in VSMCs infected with prelamin-A adenovirus (Liu et al., 2013). The group performed microarray assays and found that DNA repair pathways responsible for the removal of DSBs were downregulated, suggesting that prelamin-A accumulation amplifies the DDR against DSBs. They also verified that the miRNA-141-3p levels were increased. This microRNA negatively regulates the ZMPSTE24, a prelamin-A maturation enzyme, which was considered a significant regulator of dysfunctional VSMCs from FPLD2 subjects. Although DNA repair pathways were not assessed in detail in this work, it is reasonable to suggest that the disrupted redox homeostasis found in those subjects could induce oxidized DNA damage and contribute to the pathophysiology of FPLD2. Indeed, Maynard and co-workers investigated the mechanism by which Lmna regulates the repair of oxidized DNA damage by the BER pathway in a mice model. They performed microarray gene expression and found that Lmna ^-/- MEFs (mouse embryonic fibroblasts) displayed an upregulation of genes related to the BER pathway and mitochondrial genome maintenance (Maynard et al., 2019). On the contrary, genes involved with metabolic processes and oxidative stress response mediated by NFE2L2 (nuclear factor erythroid 2-like 2; also termed NRF2) were downregulated. However, the authors did not explore the downregulated genes related to the metabolic process. Furthermore, they found that Lmna ^-/- MEFs were sensitive to DNA damage induced by hydrogen peroxide (H₂O₂) and menadione compared to Lmna ^+/+ MEFs. Besides, the levels of 7,8-dihydro-8-oxoguanine (8-oxoG), the most abundant oxidized DNA level mainly repaired by the 8-oxoG DNA glycosylase (OGG1) from BER (Cadet et al., 2003; Krokan and Bjørås, 2013), were higher in Lmna ^-/- MEFs relative to Lmna ^+/+ MEFs after H₂O₂-induced DNA damage. These data indicate that this lesion is less efficiently repaired in the absence of Lmna, corroborating with results obtained by Comet assay, which revealed the repair efficiency of oxidized DNA lesions, including 8-oxodG and FapyG, was decreased in Lmna ^-/- MEFs relative to Lmna ^+/+ MEFs. After H₂O₂-induced DNA damage, Lmna ^-/- MEFs also showed lower levels of Parp-1, Lig3, and Polβ mRNA expression as well as lower protein levels of PARP-1, LIG3, and Polβ. Interestingly, Lmna is required to APE1 and Polβ activities, which were PARP-1 dependent. Lmna depletion by siRNA also led to impaired BER in U2OS cells. Taken together, although these findings are very relevant to unravel the role of LMNA in the repair of oxidized DNA lesions, a link between BER and LMNA in the context of adipose tissue was not provided.

The LMNA gene and HGPS

Recent evidence revealed that accumulation of progerin causes defects in the expression and recruitment of DNA repair components, in addition to the suppression of Poly-ADP-ribose polymerase 1 (PARP-1) (Liu et al., 2011; Zhang et al., 2014). Zhang and co-workers found PARP-1 suppression in smooth muscle cells (SMCs) obtained from HGPS at protein levels and by immunofluorescence. This result was confirmed in HGPS fibroblasts carrying the pathogenic variant c.1824 C>T (p.G608G). Co-expression of PARP-1/GFP in SMCs revealed that progerin induces a mislocalization of a PARP-1 fraction to the cytosol (Zhang et al., 2014). PARP-1 usually plays a role in suppressing the NHEJ DNA repair mechanism and protecting HR (Broers et al., 2006; Bertrand et al., 2011; Patel et al., 2011; Zhang et al., 2014). Besides, most SMCs from HGPS individuals activated the error-prone NHEJ repair during S-phase, while HR was deficient during S-phase, leading to mitotic disaster and cell death (Zhang et al., 2014). These data indicate the role of progerin in regulating PARP-1 expression and NHEJ activity in SMCs from HGPS individuals.

The DDR to DSBs begins with the activation of ATM (Ataxia-Telangiectasia mutated) and ATR (ATM-and Rad3-related), which play central roles in DNA repair checkpoints. ATR is activated by broad DNA damage, whereas ATM is activated by DSBs. Activated ATM and ATR phosphorylate Chk-1 (Checkpoint kinase 1) and Chk-2 (Checkpoint kinase 2), initiating the signaling cascade that leads to p53 phosphorylation (Sancar et al., 2004; Li and Zou, 2005). Liu et al compared aged HGPS fibroblasts harboring the pathogenic variant c.1824 C>T and normal BJ fibroblasts to determine whether DNA damage pathway checkpoints were persistently activated. In this study, it was observed that progeroid cells showed more frequent DSBs, and persistent activation of ATM and ATR checkpoints, which led to higher levels of phosphorylated Chk-1 and Chk-2 and, consequently, higher levels of phosphorylated p53 (Liu et al., 2006).

Another study observed that although some DNA repair proteins, such as ATM, ATR, Chk1, Chk2, and p53 were activated, Rad50 and Rad51 were not recruited to the DNA damage regions (Liu et al., 2008). Furthermore, surprisingly, XPA (Xeroderma pigmentosum complementation group A), a NER protein, was present in chromatin regions where DSBs had occurred in progeroid cells (Liu et al., 2008). The same was not observed in normal BJ fibroblasts, even when DSBs in DNA was induced by camptothecin (CPT). These findings suggest that the binding of XPA in DSBs regions prevents the recruitment of repair proteins such as Rad50 and Rad51 (Liu et al., 2008). In this way of thinking, XPA depletion was performed to verify whether the recruitment of repair proteins was restored. Indeed, a partial restoration of proteins such as Rad50, Rad51, and Ku70 was observed (Liu et al., 2008).

Mitochondrial dysfunction and increased levels of ROS were also found in HGPS fibroblasts (Richards et al., 2011). Accumulation of misrepaired DSBs and increased sensitivity to DNA damage agents, such as H₂O₂, were observed in HGPS fibroblasts. The treatment with N-acetyl cysteine (NAC), a ROS scavenger, decreased DSBs and improved cell growth (Richards et al., 2011). Besides, Kubben and co-workers found that although NFE2L2 (NRF2) protein levels did not change in HGPS fibroblasts, progerin sequesters NFE2L2 (NRF2), reducing its transcriptional activity since the sequestered NRF2 is mislocated to the nuclear periphery (Kubben et al., 2016).

The LMNA gene and MADA

To investigate the role of the LMNA R527H pathogenic variant in the cell cycle control and DDR, Alessandra di Masi and co-workers analyzed the response of MADA fibroblasts to DNA damage induced by IRa (Di Masi et al., 2008). They found high levels of chromosome aberrations in G2-irradiated MADA fibroblasts, suggesting the occurrence of misrepaired DNA and that MADA cells are more sensitive to IRa than control fibroblasts. Basal levels of phosphorylated ATM (at S1981) were higher in MADA fibroblasts. Furthermore, increased phosphorylated ATM-S1981 foci were observed in almost 70% of MADA fibroblasts after X-ray treatment, suggesting accumulated DNA damage. Besides, as phosphorylation of γ-H2AX occurs around DSBs, being considered a marker for DSBs, immunofluorescence staining with the γ-H2AX antibody was performed. MADA cells presented a higher level of γ-H2AX after IRa treatment relative to control cells (Di Masi et al., 2008). Furthermore, p53 basal levels were 2-fold higher in MADA fibroblasts compared to control, suggesting that the prelamin-A accumulation in MADA cells can determine the persistence of misrepaired DNA damage.

The ZMPSTE24 gene and MADB

The ZMPSTE24 gene contribution to genomic stability and aging was also studied in models of progeroid phenotypes. Using Zmpste24 ^-/- MEFs, Liu and co-workers discovered that the deficiency in Zmpste24 resulted in cell cycle arrest and senescence. These cells also presented chromosomal instability and quickly accumulated DNA damage relative to controls (Liu et al., 2005). Zmpste24 ^-/- MEFs had high 53BP1 foci and increased protein levels of γH2AX, a marker of DSBs, and phosphorylated chk1 (p-chk1), involved with DNA damage checkpoint response. They also found similar results in fibroblasts obtained from HGPS individuals. Zmpste24 ^-/- MEFs also were sensitive to DNA-damage agents, such as those inducing DSBs [mitomycin (MMC), methylmethanesulfonate (MMS), CPT, and etoposide] and UV. After γ-irradiation, the number of γH2AX/53BP1 co-localized foci were delayed in Zmpste24 ^-/- MEFs, suggesting that 53BP1 recruitment is affected. Besides, six and twelve hours after γ-irradiation, most of the 53BP1 foci disappeared in WT MEFs and fibroblasts. On the contrary, γH2AX/53BP1 co-localization was kept in Zmpste24 ^-/- MEFs and HGPS fibroblasts, suggesting misrepaired DSBs. Later, they investigated whether defective DNA repair is associated with ZMPSTE24 deficiency. Using comet assay, the authors showed that Zmpste24 ^-/- MEFs and HGPS fibroblasts had higher tail moment relative to controls, indicating that loss of Zmpste24 and progerin compromised DNA repair. It was also suggested that DNA repair deficiency in Zmpste24 ^-/- MEFs and HGPS fibroblasts may be due to decreased Rad51 foci formation. In another study, Varela and co-workers found that liver and heart from Zmpste24 ^-/- mice displayed an upregulation of p53 target genes, such as Gadd45a, p21 (Cdkn1a), and Atf3, as well as increased levels of γ-H2AX in the liver. Zmpste24 deficiency also resulted in a senescent phenotype (Varela et al., 2005). Taken together, the authors revealed that the accumulation of farnesylated prelamin-A due to Zmpste24 deficiency results in DNA damage accumulation, and the Rad51 recruitment is defective after γ-irradiation.

The ERCC8 (CSA), ERCC6 (CSB), and XPA genes and CS

Progressive loss of sWAT was observed in a model of CS mice (Brace et al., 2013). CS is characterized by neurodegeneration, growth failure, and photosensitivity (Fousteri & Mullenders, 2008; Vessoni et al., 2020). Csa ^-/- /Xpa^-/- (CX) mice showed more severe NER progeria, including small size and progressive loss of sWAT but not BAT. These mice also presented low levels of plasm triglycerides (TGs) and glucose. Therefore, the CX mice were a good model for studying human progeria. Later, the same group revealed changes in adiposity and lipid and glucose homeostasis in the CX mice model under chronic DNA damage induction, including IRa, crosslinking agent mitomycin (MMC), and ultraviolet (UV) radiation (Brace et al., 2016). They investigated how DNA damage affects energy metabolism and found that CX mice had a loss of sWAT and perigonadal WAT, as well as a decline in mature adipocyte size without inflammatory signals (crown-like - CL structures). Fasted CX mice had low glucose, insulin, HOMA-IR (homeostasis model assessment-estimated insulin resistance), and TGs in plasma compared to control mice. Circulating leptin levels were also decreased (Brace et al., 2016).

Another study also investigated the mitochondrial fatty acid oxidation (FAO) rate in these CX mice models. They found increased oxygen consumption rate (OCR), reduced respiratory exchange ratio (RER), as well as an upregulation of FAO-related genes in muscle from fasted CX mice (Brace et al., 2016). They also verified the impact of DNA damage on FAO capacity. For this, they used mouse dermal fibroblasts (MDFs) isolated from tails of WT and CX mice, preadipocytes for CX mice, and human dermal fibroblasts (HDFs) from CSA and CSB patients. They confirmed an increase in FAO under UV-C treatment for the CX and CS models, as well as that MMC and IRa at high doses promoted a similar rise in FAO in CX MDFs, as they found for UV-C. These results suggested that increased FAO was a beneficial adaptive response to genotoxic stress induced by UV-C, MMC, and IRa and revealed a link between genotoxic stress and energy metabolism related to DNA damage.

Furthermore, they showed that the ATP levels were decreased after UV-C or MMC treatments in WT MDFs and HDFs, which returned to normal levels almost 90 minutes later, indicating increased energy demands after the genotoxic stress induction. Interestingly, they also verified whether the ATP-reduced levels were linked to nicotinamide adenine dinucleotide (NAD⁺) depletion levels. NAD⁺ is a vital metabolite coenzyme for crucial metabolic pathways, such as glycolysis, TCA, and OXPHOS, as well as for ADP(ribosyl)ation reactions mediated by PARP-1 activity (Fouquerel and Sobol, 2014; Hurtado-Bagès et al., 2020). They found a reduction in NAD⁺ levels in WT MDFs after both UV-C and MMC treatments, which is in accordance with ATP low levels. They also assessed PARP-1 activation through PAR accumulation to better understand whether the PARP-1 activity is associated with ATP and NAD⁺ depletion in WT and PARP-1 KO MDFs under genotoxic stress. They confirmed the occurrence of an increased PARylation in WT MDFs after two different genotoxic stresses (UV-C and MMC), but not in PARP-1 KO MDFs. In addition, they found that phosphorylated adenosine monophosphate (AMP)-activated protein kinase (pAMPK), which regulates metabolic changes due to ATP depletion, was also increased in a PARP-1 dependent manner in MDFs, and this result was confirmed in MDFs obtained from AMPK KO mice. Besides, CX mice showed low levels of NAD⁺ and increased levels of pAMPK in the liver. Altogether, these findings revealed that NAD⁺/ATP depletion and AMPK activation in cells/tissues from CX mice are dependent on PARP-1 and link different types of genotoxic stresses (UV-C, MMC, and IRa) to increased FAO. These data also reveal that CX mice are a model of chronic genotoxic stress and lipodystrophy due to congenital DNA repair deficiency. However, adiponectin, an important hormone produced by adipose tissue that activates AMPK phosphorylation and is reduced in congenital lipodystrophy (Antuna-Puente et al., 2010; Lima et al., 2016; Craveiro Sarmento et al., 2020), was not investigated in this cell model.

Loss of sWAT was also observed in Csb ^m/m /Xpa^-/- mice that mimic the human progeroid CS syndrome (Van Der Pluijm et al., 2007). These mice presented increased levels of TGs and glycogen accumulation and low serum glucose and IGF. Moreover, GH/IGF1 growth axis reduction was not due to reduced GH levels or pituitary abnormalities. Using transcriptome analysis, the authors found an upregulation of Lepr and Pparg genes that codify to the leptin receptor and peroxisome proliferator-activated receptor gamma, respectively. Furthermore, upregulation of genes associated with fatty acids synthesis and genes encoding antioxidant enzymes in the liver from Csb ^m/m /Xpa^-/- mice were found. In contrast, genes involved in glycolysis, TCA, OXPHOS, and controlling growth (Igf1) were downregulated. A similar loss of sWAT was similarly found in Csb ^m/m /Xpc^-/- mice. The authors also compared the Csb ^m/m /Xpa^-/- mice model with naturally aged mice. They found that the latter also presented accumulation of glycogen and TGs, and repression of genes related to oxidative metabolism and the IGF axis (Van Der Pluijm et al., 2007).

Kamenisch and co-workers revealed that the presence of CSA and CSB proteins in mitochondria are essential for protecting against loss of sWAT (Kamenisch et al., 2010). After H₂O₂ treatment, oxidatively stressed WT fibroblasts had detectable levels of CSA and CSB within mitochondria. Further, they detected interactions between CSA or CSB and mitochondrial OGG1 (mtOGG1) and single-stranded DNA binding protein (mtSSBP1) only in H₂O₂-stressed WT cells. Cells from CSA and CSB patients and sWAT from Csb ^m/m and Csa ^-/- mice showed higher levels of mutations in mtDNA that was age-dependent. Fat tissue from 130-weak-old Csb ^m/m mice had a higher accumulation of mtDNA mutations. They also investigated whether the reduction of sWAT in Csb ^m/m mice was due to a reduction in the fat cell size or number. They found that sWAT from 130-weak-old Csb ^m/m mice had higher levels of macrophages containing granular lipofuscin in lysosomes, a phagocytosis marker, suggesting that the loss of sWAT in Csb ^m/m and Csa ^-/- mice is mediated on the fat number (Kamenisch et al., 2010). However, the authors did not investigate the metabolic parameters nor the levels of antioxidant adipokines, such as adiponectin, in Csb ^m/m and Csa ^-/- mice. It is known that mitochondrial function is crucial for adiponectin synthesis in adipocytes (Eun et al., 2007), adiponectin is downregulated in lipodystrophies (Antuna-Puente et al., 2010), and this adipose tissue-produced hormone induces antioxidant responses through NRF2 activation (Li et al., 2015; Ren et al., 2017). However, whether adiponectin is involved with the maintenance of mtDNA homeostasis in lipodystrophies remains to be shown.

The ERCC4 (XPF) and ERCC1 genes and XP

Another association between DNA repair deficiency, absence of adipose tissue, and aging was also found (Niedernhofer et al., 2006). The authors used the Ercc1 ^-/- mice model as an accurate model of an XPF-ERCC1 (XFE) progeroid patient. They found that Ercc1 ^-/- mice presented weight loss, and the primary mouse embryonic fibroblasts isolated from these mice were sensitive to oxidative stress induced by treatment with H₂O₂ and paraquat. They showed premature aging in several organs and had liver failure. As in the Csb ^m/m /Xpa^-/- mice model, a transcriptomic analysis from Ercc1 ^-/- mice liver revealed an upregulation of genes associated with fatty acids synthesis and genes encoding antioxidant enzymes. Furthermore, Lepr and Pparg genes were upregulated, and the Adipor2 (adiponectin receptor 2) was downregulated. On the contrary, low levels of glucose and IGF were also found in this cell model. Taken together, these findings show that both models of NER progeria are associated with loss of adipose tissue homeostasis, and this can be due to the accumulation of ROS and DNA damage accumulation. This results in the downregulation of GH/IGF1 hormonal axis in Ercc1 ^-/- mice to moderate the metabolism, indicating that IGF1 reduction may have beneficial effects in extending lifespan in mice. However, since DNA damage accumulates, degenerative processes will occur, such as loss of sWAT, resulting in aging. CS patients have been previously reported with low levels of IGF1 serum and decreased fat deposition (László and Simon, 1986; Park et al., 1994). As observed in Csb ^m/m /Xpa^-/- mice model, the reduction of genes related to the GH/IGF1 growth axis in Ercc1^-/- mice liver was also not due to reduced GH levels or pituitary abnormalities.

In the same way, Karakasilioti and co-workers provided evidence for a causal link between persistent DNA damage and the gradual appearance of progressive lipodystrophy in NER progeria (Karakasilioti et al., 2013). To increase the understanding of the role of unrepaired DNA damage in adipose tissue degeneration, they found that DNA damage signaling resulted in fat depletion due to chronic inflammation in Ercc1 ^-/- fat depots from mice or in adipocytes (Karakasilioti et al., 2013). These mice presented a gradual reduction of epididymal WAT (eWAT), cervical, interscapular, and sWAT depots. To distinguish primary and secondary mechanisms related to fat depletion in Ercc1-deficient mice, the authors also created aP2-Ercc1 ^F/- mice, which present aP2 expression mainly but not exclusively in mature adipocytes (Shan et al., 2013), while Ercc1 is later deleted. This strategy aims to verify the effect of time-dependent accumulation of DNA damage only on adult AT depots. Progressive lipodystrophy was also found in eWAT, interscapular, and sWAT from aP2-Ercc1 ^F/- mice, which had high TGs and low levels of adiponectin. They also had decreased interscapular BAT depots.

To further understand the role of ERCC1 in WAT, the authors analyzed the transcriptome of eWAT depots and found more than 2.000 differentially expressed genes. Genes related to response to DSBs (for ex. ATM signaling), response to stress (for ex. NRF2-related oxidative stress response), nuclear receptor (for ex. PPAR), and pro-inflammatory (TNF, NFκB) signaling were upregulated. Accumulation of γ-H2AX, phosphorylated ATM (pATM), RAD51, and FANCI was observed in adipocytes from aP2-Ercc1 ^F/- mice. Ablation of Ercc1 also triggered a gradual accumulation of persistent DNA damage, resulting in adipocytes’ necrosis.

The BANF1 gene and NGPS

Barrier-to-autointegration factor 1 (BANF1) is another protein related to severe premature aging and DNA damage/repair in NGPS (Bolderson et al., 2019; Rose et al., 2021). This protein is essential for controlling the DDR against oxidative stress by regulating PARP-1 activity (Bolderson et al., 2019). The authors found that skin fibroblasts from NGPS subjects harboring the c.34 G>A (p.A12T) pathogenic variant in the BANF1 gene had decreased PARP-1 poly-ADP-ribose activity and repair of oxidized DNA lesions induced by H₂O₂. Biochemical experiments in HEK293T cells revealed that the mutated BANF1 protein directly inhibits PARP-1 activity by binding to its NAD⁺ binding domain, maintaining the cellular levels of NAD⁺ after DNA damage induction. They concluded that the subcellular levels of the BANF1 protein are critical to reset PARP-1 activity under oxidative stress conditions, and the accumulation of oxidized DNA damage is associated with HGPS development. Figure 1 shows the main molecular findings concerning PARP-1 activity in different cellular models of progeroid lipodystrophy (HGPS, NGPS, and CS).

Figure 1 -
Modulation of PARP-1 activity in HGPS, NGPS, and CS. (A) In smooth muscle cells (SMCs) and fibroblasts from HGPS individuals, progerin accumulation results in suppression of PARP-1 protein levels. SMCs activated the error-prone NHEJ repair during S-phase, while HR was deficient during S-phase, leading to mitotic disaster and cell death (Zhang et al., 2014). (B) Following H₂O₂-induced oxidative stress in HEK293T cells, the mutated BANF1 protein interacts with the NAD⁺-binding domain of PARP-1, directly regulating its ADR-ribose (ADPr) activity. Furthermore, NGPS fibroblasts showed decreased PARylation and repair of H₂O₂-induced DNA lesions (Bolderson et al., 2019). (C) In CX mice liver, increased FAO, low levels of NAD⁺, and increased levels of pAMPK were found. These findings revealed that NAD⁺/ATP depletion and AMPK activation in cells/tissues from CX mice are dependent on PARP-1 (Brace et al., 2012, 2016). Pieces of this image are from the SMART website (Les Laboratoires Servier).

The POLD1 gene and MDPL

A multisystem disease characterized by mandibular hypoplasia, deafness, progeroid features, and lipodystrophy (MDPL) was associated with pathogenic variants in the POLD1 gene in seven patients (Shastry et al., 2010). Two MDPL patients from this work (named 300.4 and 500.4) were also described by Shastry and co-workers (named P3 and P4) (Weedon et al., 2013) (Shastry et al., 2010). Shastry and co-workers found a progressive loss of sWAT with partial lipodystrophy in four young adults, while generalized lipodystrophy was confirmed only in older patients. Weedon and co-workers found that, although the patients presented normal body weight and appearance at birth, they had a lack of sWAT in early childhood. Loss of sWAT in adulthood was observed in almost all sites, which contrasted with a remarkable increase of vWAT, resulting in a greater ratio of vWAT to sWAT (Weedon et al., 2013). They also presented IR, fibrosis of sWAT, and increased levels of fundamental extracellular matrix (ECM) genes, such as transforming growth factor (TGF)-β (TGFB1) and fibronectin (FN1) (Weedon et al., 2013). They identified an in-frame deletion c.1812-1814delCTC (p.Ser605del) in the POLD1 gene in two patients, which affects the polymerase’s active site. Assays for measuring the polymerase and exonuclease activities revealed that the heterozygous in-frame deletion affected the polymerase activity, which was not detectable, whereas the exonuclease activity was decreased. Another study reported a novel pathogenic variant in the exonuclease domain of the POLD1 gene (p.Arg507Cys). However, they did not perform functional experiments to characterize better how the activities of POLD1 are affected. In this case, the MDPL patient also had a loss of sWAT nearly in the entire body, except for mechanical adipose tissue (Pelosini et al., 2014). Reinier and co-workers also described a patient harboring the c.1812-1814delCTC (p.Ser605del) pathogenic variant in the POLD1 gene who had severe lipodystrophy and progeroid features (Reinier et al., 2015). The exact pathogenic variant was also found in Japanese subjects for two independent groups, suggesting that c.1812-1814delCTC (p.Ser605del) is a deletion hot spot variant associated with MDPL (Okada et al., 2017; Sasaki et al., 2018). Wang and co-workers reported the same family with subjects harboring two rare progeroid diseases, WS and MDPL (Wang et al., 2018). The proband had the hot spot c.1812-1814delCTC (p.Ser605del) pathogenic variant in the POLD1 gene. He presented a progressive loss of sWAT and progeroid features that started at 18 months. His three brothers who had WS showed a heterozygous frameshift pathogenic variant in the WRN gene (c.919_923delACTGA, p.Thr307ThrfsX5) (Wang et al., 2018). Another MDPL case due to the hot spot heterozygous in-frame deletion was also described in a Chinese patient who presented progressive loss of sWAT that started at the age of seven (Yu et al., 2021).

Elouej and co-workers described a new heterozygous pathogenic variant affecting the zinc finger 2 (ZNF2) domain in the POLD1 gene (c.3209 T>A; p.Ile1070Asn) (Elouej et al., 2017). The patient developed lipodystrophy and progeroid facial features. Predictions using the PredictProtein server suggested that the substitution of isoleucine by asparagine at position 1070 can disrupt the Fe-S cluster within the CysB motif from the ZNF domain. Furthermore, Ajluni and co-workers also reported a new pathogenic variant affecting the ZNF2 domain (c.3199 G>A; p.Glu1067Lys). However, in this case, the two related subjects had reduced sWAT in the extremities but not around the neck, face, and abdominal wall. They presented IR, elevated CK levels, and proteinuria. They did not show progeroid features and deafness. In addition, while the MDPL patient had a high amount of nuclear atypia and disorganization in liver biopsy samples, these changes in the nuclear envelope integrity were lower when compared to patients harboring LMNA-pathogenic variants (p.R60G, p.R482Q, and p.R349W) (Ajluni et al., 2017).

Mechanistically, two independent works found that the progeroid features of two MDPL patients harboring the in-frame heterozygous deletion p.Ser605del are related to impaired DNA repair capacity (Fiorillo et al., 2018; Murdocca et al., 2021). Fiorillo and coworkers found that an MDPL patient carrying the heterozygous single codon deletion c.1812-1814delCTC (p.Ser605del) in the POLD1 gene showed type 2 diabetes, hyperinsulinemia, and IR. HDFs obtained from this patient had nuclear envelope abnormalities, intranuclear accumulation of prelamin-A, high levels of micronuclei, cellular senescence, and growth decline. The authors studied the link between MDPL and DNA damage accumulation. After cisplatin-induced DSBs, they found high levels of γH2AX foci and a DNA repair recovery delay in HDFs compared with WT HDFs (Fiorillo et al., 2018). Similar results were found in HDFs obtained from a second MDPL patient (Murdoccaet al., 2021).

Although all these findings ratified the role of POLD1 in adipose tissue homeostasis, our understanding of how these pathogenic variants result in cellular defects in adipose tissue is scarce, and the mechanisms that link disrupted POLD1 activity to different diseases need to be further clarified.

The RECQL2 (WRN) and RECQL3 (BLM) genes and WS and BS

WS and BS have been studied as a model for deciphering adipose tissue senescence. Using CRISPR/Cas9, Goh and co-workers generated WRN ^-/- and BLM ^-/- human pluripotent stem cells (hPSCs), which were differentiated in adipocyte precursors (APs) (Goh et al., 2020). They found that WRN ^-/- and BLM ^-/- APs displayed reduced cell proliferation, shorter telomeres, and senescence. The latter was confirmed by measuring the mRNA levels of the senescent biomarkers: p16, p21, Activin A, IL-6, and IL-8. These findings suggest that preadipocyte senescence may be the cause of metabolic complications in WS and BS. In another study, Turaga and co-workers transfected human diploid fibroblasts with a siRNA against WRN mRNA, which became senescent and presented a similar gene expression profile relative to fibroblasts established from old donor patients (Turaga et al., 2009). From 660 differentially expressed genes found in the microarray analysis, 542 (82%) were downregulated, whereas 118 genes (18%) were upregulated, revealing a repression scenario in cells with lower WRN levels. Western blotting was performed for fourteen proteins and they confirmed the downregulation of: CCNB1 (Cyclin B1), CDC2 (Cyclin-dependent kinase 1), FANCD2 (Fanconi anemia complementation group D2), FANCI (Fanconi anemia complementation group I), FANCJ (Fanconi anemia complementation group J), FAS (Fas cell surface death receptor), HUWE1 (E3 ubiquitin-protein ligase), MRE11A (Meiotic Recombination 11 homolog A), KIF4A (Kinesin family member 4A), LMNA (Lamin A/C), MAPK8 (Mitogen-activated protein kinase 8), POLD1 (DNA polymerase δ subunit 1), SAFB1 (Scaffold attachment factor B1), and TOP2A (Topoisomerase II alpha). The gene set enrichment analysis revealed that the genes related to adipocyte differentiation were downregulated in WRN-knockdown fibroblasts (Turaga et al., 2009). To confirm this observation, the authors also transfected the 3T3-L1 mice preadipocytes with a siRNA against Wrn mRNA. The expression of adipogenic markers, such as C/EBPβ (CCAAT/enhancer binding protein β) and fatty acid synthase (FASN), was decreased. These data link the role of WRN and BLM proteins in the maintenance of adipose tissue homeostasis.

The POLR3A gene and WRS

The POLR3A gene is crucial for cell function and metabolism. Pathogenic variants can alter its ability to interact with DNA, causing drastic changes in its transcriptional function and RNA polymerase I and II regulation. This scenario is associated with an early senescent phenotype found in primary WRS fibroblasts carrying the pathogenic variant c.3772_3773delCT (p.Leu1258Glyfs*12) in the POLR3A gene. WRS fibroblasts presented increased expression levels of the mutant POLR3A protein in the nucleoplasm, which was not expressed in control fibroblasts. Senescence was revealed by the presence of higher beta-galactosidase-positive WRS cells and increased levels of p16 protein expression. Decreased telomere length, increased DNA damage, and variations in the morphology and number of nucleolus were also seen (Báez-Becerra et al., 2020). WRS fibroblasts exhibited strong phosphorylation levels of H2X in the Ser139 (termed γH2AX) and p53 (in the Ser15) relative to control cells, which were associated with increased nuclear staining. These results indicate that WRS fibroblasts show an increase in DNA damage that can induce DDR and, consequently, a p53-mediated cell senescence. Also, a pathway of POLR3-mediated p53 regulation is likely lost upon POLR3A pathogenic variants in WRS fibroblasts. Altogether, these results revealed a link between POLR3A variants and DDR in WRS fibroblasts.

The SPRTN gene and RJALS

Lessel et al. (2014), proposed a clinical study of three patients with early-onset hepatocellular carcinoma (HCC), genomic instability, and progeroid features. To analyze Spartan function in DNA damage, U2OS cells were depleted of endogenous SPRTN using siRNA. Later, these SPRTN knockdown cells were transfected with the WT SPRTN, the mutant p.Tyr117Cys SPRTN, or ∆C-TER SPRTN. The authors found that the WT and mutated p.Tyr117Cys SPRTN formed nuclear foci, but not the mutated ∆C-TER SPRTN. The histological and immunohistochemical investigation of the patients’ liver tumor biopsies showed an increased accumulation of γH2AX and 53BP1 after CPT treatment, a chemotherapeutic agent that induces DPCs, including Top1 cleavage complex (Top1ccs). This result was also confirmed in SPRTN-knockdown U2OS cells expressing the mutant p.Tyr117Cys SPRTN and ∆C-TER SPRTN. Severe growth defects were also observed in patient fibroblasts, which showed increased levels of DSBs when in the S-phase. Indeed, transfection of patient fibroblasts with WT SPRTN efficiently corrected the replication defects and reestablished cellular proliferation. These results revealed that cells expressing mutant SPRTN were unable to recover DNA replication fork progression, leading to DNA replication stress and replication-related DNA damage, especially DSBs (Lessel et al., 2014). In the same year, Maskey et al. (2014) demonstrated that γH2AX foci, a marker of DNA damage, were markedly increased in Sprtn ^F/- MEFs after 4-hydroxytamoxifen (4-OHT) treatments, and that Sprtn ^-/- MEFs had increased numbers of 53BP1 nuclear bodies, indicating incomplete DNA replication.

To better characterize the molecular mechanism by which SPRTN contributes to genomic stability, Lopez-Mosqueda et al. (2016) verified the role of SPRTN in resolving DPCs. They found that SPRTN-KO MEFs were sensitive to agents that induce DPCs, such as formaldehyde, etoposide, and CPT. Also, B-II-1 lymphoblastoid cells derived from RJALS were sensitive to those DPCs-inductor agents. These cells also exhibited more γ-H2AX staining after formaldehyde and etoposide treatments (Lopez-Mosqueda et al., 2016). They also confirmed that SPRTN is a DNA binding protease involved with the removal of DPCs in vivo and in vitro. These data are consistent with accelerated aging phenotypes observed in the hypomorphic SPRTN mouse model, linking DPC repair deficiency to segmental progeroid syndrome (Lopez-Mosqueda et al., 2016).

Vaz et al. (2016) confirmed that SPRTN protease is a protein specialized in the repair of DPCs, being essential for DNA replication progression and genome stability. They found that RJALS patient cells and SPRTN-depleted cells were hypersensitive to agents inducing DPCs. Besides, HeLa cells transfected with ∆-SPRTN showed a higher average number of 53BP1 foci relative to controls after CPT treatment. This was observed only in cyclin A-positive ∆-SPRTN HeLa cells, suggesting a role of SPRTN in preventing DSBs induced by DPCs during the S-phase. Thus, RJALS cells are unable to process DPCs during DNA replication, leading to DNA replication stress, one of the main causes of genome instability and cancer (Vaz et al., 2016).

Maskey et al. (2017) used Sprtn hypomorphic MEFs, which express reduced levels of Spartan but have a normal cell-cycle distribution, to verify the role of Spartan in the repair of Top1ccs, a bulky CPT-induced DPC that blocks replication forks. They found that Sprtn hypomorphic MEFs exhibited high CPT sensitivity compared to control MEFs, suggesting that Spartan may play a role in Top1ccs repair. Furthermore, they studied the effects of DPCs in Sprtn hypomorphic mice, which recapitulate phenotypes observed on RJALS. They found an accumulation of Top1ccs in the liver, indicating an increased binding of Top1 to DNA (Maskey et al., 2017). Therefore, given that Spartan plays a significant role in DNA stability by being responsible for DPC repair throughout DNA replication, pathogenic variants in the SPRTN gene affect DNA repair and are associated with hepatocellular carcinoma and premature aging, such as in RJALS.

Figure 2 shows a model depicting the occurrence of unrepaired DSBs and persistent γ-H2AX in some progeroid diseases with remarkable loss of sWAT. As reviewed here, activation of DDR in HGPS, MADA, MADB, WRS, RJALS, and MDPL was seen, revealing an association among DSBs’ accumulation, aging, and loss of sWAT. Indeed, the role of p53 in the maintenance of sWAT homeostasis during aging was confirmed by Liu and co-workers (Liu et al., 2018). Using adipocyte-specific MDM2-knockout mice (Adipo-MDM2-KO), the authors found that MDM2 mRNA and protein levels are selectively downregulated in sWAT and BAT, while p53 and p21 were induced in both AT depots. Adipose senescence and apoptosis were observed in aged adipose tissue, and adipocytes had an aberrant expression of pro-inflammatory cytokines, such as TNFα and IL-6, while the p21 senescent marker was increased. Furthermore, adipocytes from old Adipo-MDM2-KO showed remarkable and progressive loss of SWAT, eWAT, and BAT, and leptin and adiponectin levels were nearly undetectable, revealing an early onset of lipodystrophy in this mice model. These mice also had diabetes, fatty liver, and higher levels of TGs, insulin, and glucose in plasma. The role of p53 in adipocytes’ homeostasis was validated by the generation of a DKO mice model lacking p53. DKO mice showed a rescued phenotype of sWAT loss and improvement of the metabolic parameters, confirming that the p53 activation is related to the MDM2-null phenotypes. However, the contribution of DNA damage/repair to the MDM2-p53 axis in the Adipo-MDM2-KO mice model was not assessed.

Figure 2 -
The main DNA repair changes in progeroid diseases with remarkable loss of sWAT depicting the occurrence of unrepaired DSBs and persistent γ-H2AX. (A) In HGPS, progerin accumulation results in frequent DSBs, phosphorylation of ATM, ATR, Chk1, Chk2, and p53 (Liu et al., 2006). XPA binding to or near DSBs impairs Rad50 and Rad51 recruitment to damaged DNA (Liu et al., 2008). Furthermore, accumulated progerin sequesters NRF2, attenuating its transcriptional activity (Kubben et al., 2016). (B) Increased levels of DSBs are also found in HGPS, MADA, MADB, MDPL, RJALS, and WRS, revealing a common DDR activation by phosphorylation of ATM and p53 (Liu et al., 2005; Di Masi et al., 2008; Maskey et al., 2014; Lessel et al., 2014; Fiorillo et al., 2018; Báez-Becerra et al., 2020; Murdocca et al., 2021). This mechanism is involved with senescence and apoptosis (Smith et al., 2021). Pieces of this image are from the SMART website (Les Laboratoires Servier).

Adipose tissue-related genes associated with changes in the expression of dna repair and Oxidative stress genes

The BSCL2 gene and CGL2

The ER-localized seipin, an adipose tissue-related protein involved with LDs assembly (Wang et al., 2016), was associated with changes in redox homeostasis (Craveiro Sarmento et al., 2020). The authors verified that blood leukocytes from CGL2 individuals carrying the pathogenic variant c.325dupA (p.T109Nfs*5) in the BSCL2 gene displayed higher levels of serum oxidized glutathione and malondialdehyde, indicating the occurrence of oxidative stress and lipid peroxidation on blood from individuals presenting a paucity of sWAT since birth. Using LX-PCR to quantify the levels of mitochondrial DNA (mtDNA) damage, they found that the number of mtDNA lesions obtained from blood leukocytes from CGL2 subjects was higher relative to the control groups. Besides, the levels of mtDNA lesions were positively correlated with NFE2L2 (NRF2) mRNA levels, suggesting the activation of NRF2 antioxidant responses. A positive correlation was also found between NRF2 mRNA and serum adiponectin levels. Even in low levels in CGL2 subjects, this finding suggests that NRF2 activation occurred in an adiponectin-dependent manner. More studies are needed to unravel the relationship between NRF2 and adiponectin in the context of loss of sWAT.

Moreover, mitochondrial bioinformatics predictions by Mitochondrial Disease Database (MITODB) (Scheibye-Knudsen et al., 2013), a software that determines whether a disease could be associated with mitochondrial commitments according to its phenotypes, revealed that CGL2 has a high probability (mito-score 92) of being related to mitochondrial disturbs since its clinical spectrum includes lipodystrophy, hepatomegaly, HTG, muscle hypertrophy, muscle hyperplasia, hypertrophic cardiomyopathy, and bone cysts (Lima et al., 2016). These findings are in accordance with recently published data (Combot et al., 2022), who found that seipin is localized at ER-mitochondria sites and has a role in the Ca²⁺ importation to mitochondria. However, how this protein regulates changes in redox homeostasis in CGL2 subjects needs more investigation.

Since mtDNA lesions were higher and upregulation of NRF2 mRNA was found in CGL2 subjects, Craveiro-Sarmento et al. (2019) investigated whether the BER pathway could be regulated in blood leukocytes. These cells displayed higher mRNA levels of APEX1, OGG1, and OGG1α, and the latter is expressed both in the nucleus and mitochondria and has an essential role in the maintenance of mitochondrial functions (Lia et al., 2018). Table 2 summarizes the main findings of this topic.

The CAV1 gene and a severe neonatal progeroid and lipodystrophy syndrome

Whole blood from a subject harboring the heterozygous pathogenic variant c.479_480delTT and c.51_52insGTC in the CAV1 was associated with a severe neonatal progeroid and lipodystrophy syndrome. The 3-year-old patient also presented a heterozygous variant c.51_52insGTC in the AGPAT2 gene. The contribution of the latter to the development of this lipodystrophic progeroid disease is unclear. The 3-year-old patient showed severe loss of sWAT, progeroid features, and high levels of TGs in infancy. Fibroblasts isolated from this subject displayed lower levels of the caveolin-1 protein relative to the controls. RNA-seq analysis suggested a downregulation of LMNA, ATM, RECQL4, and WRN genes in the whole blood cells from this subject. Furthermore, the Fanconi anemia pathway was also downregulated. However, experimental data were not conducted, and a list with all differentially expressed genes was not provided to confirm these findings. Table 2 summarizes the main findings of this topic.

Critical roles of DNA damage and repair in adipose tissue homeostasis

The role of DNA repair enzymes in adipose tissue homeostasis was also studied in obesity, revealing the importance of DNA integrity for maintaining the functions of WAT. In this section, we will highlight the main findings concerning the role of NEIL1 (Nei like DNA glycosylase 1) and OGG1 DNA glycosylases, from the BER pathway; ATM, which is involved with the repair of DSBs; and XPV, the DNA polymerase eta that acts bypassing the UV-induced DNA lesions, being involved with damage tolerance by translesion synthesis (Menck and Munford, 2014). Table 3 shows the main findings of this section.

Table 3 -
Genes related to DNA repair, DDR, or translesion DNA synthesis and their critical roles in adipogenesis.

Gene code (*OMIM code)	Protein name	Cell model	Changes in redox homeostasis and DNA repair	Adipose tissue and metabolic commitments	Reference
NEIL1 (*608844)	Endonuclease 8-like 1	Neil1-/- mice in the absence of exogenous oxidative stress. Neil1 -/- mice under chow diet ad libitum.	Increased mitochondrial DNA (mtDNA) damage, especially in male Neil1 -/- mice.	Severe obesity, dyslipidemia, and hepatic steatosis. Hyperleptinemia and high levels of triglycerides and insulin.	(Vartanian et al., 2006)
NEIL1 (*608844)	Endonuclease 8-like 1	Neil1-/- mice in the absence of exogenous oxidative stress. Neil1 -/- mice under high-fat diet (HFD).	Increased hepatic expression of inflammatory genes. Reduction in mitochondrial DNA.	Increased body weight and body fat accumulation, hypertriglyceridemia, and glucose intolerance. Hepatic lipid accumulation.	(Sampath et al., 2011)
OGG1 (*601982)	8-oxoguanine DNA glycosylase	Ogg1-/- mice under high-fat diet (HFD).	Downregulation of Ppargc1a, Ppargc1b and genes related to TCA cycle and fatty acid oxidation in the liver of Ogg1 -/- mice.	Higher adiposity, hepatic steatosis, impaired glucose tolerance, and higher levels of insulin and hepatic triglycerides (TGs).	(Sampath et al., 2012)
OGG1 (*601982)	8-oxoguanine DNA glycosylase	Ogg1-/- mice under high-fat diet (HFD).	Increased expression levels of fatty acid oxidation (FAO), lipid uptake, and TCA genes, Higher gene and protein levels of the mitochondrial fission proteins Drp1 and Fis1. No changes in 8-oxoG levels.	Increased lipid deposition in muscle.	(Vartanian et al., 2017)
OGG1 (*601982)	8-oxoguanine DNA glycosylase	Epididymal adipocytes (eWAT) from transgenic mice targeting OGG1 to mitochondria (Ogg1 Tg mice).	Bigger mitochondria and higher expression levels of Pgc1α, Sirt1, Tnfα, Ikkβ, and the mitochondrial fusion proteins Mfn1, Mfn2, and Opa1. eWAT from Ogg1 Tg mice seem to have lower 8-oxodG levels.	OGG1 confers protection against diet-induced obesity, insulin resistance, and adipose tissue inflammation. Decreased body composition and smaller adipocytes in eWAT in Ogg1 Tg mice under a high-fat diet (HFD). Low levels of glucose, insulin, TGs, and cholesterol in plasma and low levels of TGs and cholesterol in the liver. High expression levels of FAO genes. Lower levels of leptin and higher levels of adiponectin in plasma.	(Komakula et al., 2018)
OGG1 (*601982)	8-oxoguanine DNA glycosylase	Mouse 3T3-L1 preadipocytes expressing hOGG1a with a mitochondrial targeting sequence (MTS) and preadipocytes from Ogg1 -/- and Ogg1 Tg mice.	Increased OGG1 expression and activity during adipogenesis induction, and higher PAR levels in 3T3-L1 mouse preadipocytes expressing MTS-hOGG1a.	Attenuated expression of genes related to preadipocyte differentiation (Scd1, Pparγ, and c/ebpα) and reduced lipid accumulation in preadipocytes from Ogg1 Tg mice and 3T3-L1 cells expressing -MTS-hOGG1a. Increased expression of genes related to preadipocyte differentiation (Scd1, Pparγ, and c/ebpα) and enhanced lipid accumulation in preadipocytes from Ogg1 -/- mice.	(Komakula et al., 2021)
XPV (*603968)	DNA polymerase eta - POLH	polη-/- mice in the absence of exogenous oxidative stress. polη -/- mice under a high-fat or fructose diet.	Increased DNA damage, upregulation at both the protein and mRNA levels, and phosphorylation of ATM, H2AX, p21, and p53. Upregulation at both the protein and mRNA levels of NF-κB and PARP-1.	Severe obesity, high levels of insulin, leptin, and HOMA-IR. Increased levels at both the protein and mRNA levels of the adipogenic master regulators PPARγ and SREBP1. Adipocyte senescence.	(Chen et al., 2015)
ATM (*607585)	Ataxia telangiectasia serine/threonine kinase	Atm+/- mice and Atm +/- /ApoE-/-) mice under a high-fat diet (HFD).	Delayed activation of Chk-2 and p53. Increased levels of ROS and mtDNA damage in Atm +/- mice.	Obesity, hypertension, macrophage infiltration, and hyperlipidemia in Atm +/- mice.	(Mercer et al., 2010)
ATM (*607585)	Ataxia telangiectasia serine/threonine kinase	Atm-/- mice in the absence of exogenous oxidative stress. Atm -/- mice under a high-fat diet (HFD).	-	Lipodystrophic-like phenotype (loss of sWAT), insulin resistance, and low levels of serum leptin and adiponectin.	Takagi et al., 2015

• OMIM: Online Mendelian Inheritance in Man.

The role of NEIL1

NEIL1 was one of the first BER enzymes associated with metabolic complications (Vartanian et al., 2006). Under chow diet ad libitum, Neil1 ^-/- mice displayed severe obesity, dyslipidemia, and hepatic steatosis. These mice exhibited hepatic steatosis, hyperleptinemia, and high levels of TGs and insulin in plasma. Besides, they found increased mitochondrial DNA (mtDNA) damage and deletions, especially in male Neil1-/- mice (Vartanian et al., 2006). In another study by the same group, Neil1 ^-/- mice under chronic oxidative stress induced by a high-fat diet (HFD) displayed increased body weight and body fat accumulation, HTG, and glucose intolerance (Sampath et al., 2011). They also observed an increased hepatic expression of inflammatory genes and a reduction in mitochondrial DNA. These data demonstrated the role of NEIL1 DNA glycosylase in adipose tissue accumulation and mitochondrial dysfunction.

The role of OGG1

The role of the OGG1 BER enzyme in metabolic homeostasis has also been investigated by the Lloyd and Sampath groups (Sampath et al., 2012; Vartanian et al., 2017; Komakula et al., 2018, 2021). They first found that Ogg1 ^-/- mice were more susceptible to obesity and metabolic dysfunction relative to control mice. Under a high-fat diet (HFD), they presented higher adiposity, developed hepatic steatosis, and showed higher levels of insulin and hepatic TGs. Analysis of microarray and qPCR revealed that genes related to the TCA cycle and FAO were downregulated in the liver of Ogg1 ^-/- mice, as well as the Ppargc1a and Ppargc1b genes that codify to the PPAR-gamma coactivator-1 alpha (Pgc1α) and PPAR-gamma coactivator-1 beta (Pgc1β), respectively (Sampath et al., 2012).

Later, they verified that skeletal muscle from Ogg1 ^-/- mice show increased lipid deposition, which included TGs, cholesterol esters (CE), diacylglycerol (DAG), free fatty acids (FFAs), and phospholipids (PLs). Further, gene and protein expression of Drp1 and Fis1 proteins, which are associated with mitochondrial fission, were higher in muscle from Ogg1 ^-/- mice. Besides, the expression levels of genes regulating FAO and lipid uptake, as well as TCA, were increased relative to WT mice. No differences in 8-oxoG levels were found (Vartanian et al., 2017).

The contribution of mitochondrial OGG1 to metabolic syndrome was also investigated. Using preadipocytes from transgenic mice targeting OGG1 to mitochondria (Ogg1 ^Tg mice), they found a protective role of OGG1 against diet-induced obesity, IR, and adipose tissue inflammation (Komakula et al., 2018). They observed a decreased body weight, fat body composition, and smaller adipocytes in eWAT in Ogg1 ^Tg mice under HFD. Furthermore, Ogg1 ^Tg mice displayed low levels of glucose, insulin, TGs, and cholesterol in plasma, as well as low levels of TGs and cholesterol in the liver, suggesting that the reduced fat mass observed in Ogg1 ^Tg mice does not result in lipodystrophic lipid accumulation in the liver. eWAT of Ogg1 ^Tg mice under HFD also exhibited high expression levels of Pgc1α, Sirt1, Tnfα, Ikkβ, and FAO genes, such as Cpt-1, Acox, Hsl, Atgl, and Pparα. Lower levels of leptin and higher levels of adiponectin were also found in Ogg1 ^Tg mice plasma. Since they previously found a downregulation in Pgc1α in Ogg1 ^-/- mice (Vartanian et al., 2017), the higher levels of this transcriptional co-activator from Ogg1 ^Tg mice indicate the role of OGG1 in promoting the mitochondrial metabolism in eWAT. Additionally, since SIRT1 regulates adiponectin levels (Qiang et al., 2007), and both are increased in eWAT of Ogg1 ^Tg mice, this work also demonstrated the importance of mtOGG1 for activating the SIRT1-adiponectin axis. They also investigated whether targeting OGG1 to mitochondria changes mitochondrial morphology. They found that mitochondrial are elongated in eWAT of Ogg1 ^Tg mice and these mice presented higher expression levels of mitochondrial fusion proteins, such as Mfn1, Mfn2, and Opa-1. Although 8-oxoG levels seem to be reduced in eWAT of Ogg1 ^Tg mice under HFD, no statical differences were observed relative to WT mice. Together, these data demonstrate the metabolic protective role of targeting OGG1 to mitochondria in eWAT.

The role of OGG1 in adipogenesis and lipid accumulation was investigated (Komakula et al., 2021). Preadipocytes from Ogg1 ^-/- mice displayed increased expression of genes related to preadipocyte differentiation (Scd1, Pparγ, and c/ebpα) and enhanced lipid accumulation. On the contrary, mouse 3T3-L1 preadipocytes from Ogg1 ^Tg mice and 3T3-L1 cells expressing-MTS-hOGG1a showed attenuated expression of genes related to preadipocyte differentiation (Scd1, Pparγ, and c/ebpα) and reduced lipid accumulation. Since OGG1 activates PARP-1 (Noren Hooten et al., 2011), and PARylation inhibits adipogenesis (Devalaraja-Narashimha and Padanilam, 2010; Luo et al., 2017), they assessed the role of OGG1 on PARylation in mouse preadipocytes. While PARP-1 protein levels were higher before starting adipocytes differentiation, its levels decreased during adipogenesis induction in both 3T3-L1 cells (expressing-MTS-hOGG1a and GFP-controls), which in accordance with reduced PAR levels. However, MTS-hOGG1a cells exhibited higher PAR levels in all time points of adipocytes differentiation relative to control cells. Increased total protein PARylation was also verified in differentiated primary adipocytes and adipose tissue protein extracts from Ogg1 ^Tg mice, whereas primary adipocytes, adipose tissue extracts, liver, and BAT from Ogg1 ^-/- mice exhibited reduced levels of total protein PARylation. These findings reveal the role of OGG1 in promoting PARP-1 activity in mice. More data are needed to clarify the contribution of OGG1 in human adipogenesis.

The role of XPV

The XP-V gene encodes polymerase η (Pol η), which plays a crucial role in preventing UV radiation-induced DNA damage (5). Defects in the gene encoding to pol η produce the variant form (V type) of the autosomal recessive disease Xeroderma Pigmentosum (XP-V) (Masutani et al., 1999). XP-V patients tend to have high sensitivity to UV radiation, which often leads them to develop skin cancer (Masutani et al., 1999). Chen and co-workers demonstrated that polymerase η deficiency in mice (polη ^-/- mice) causes obesity with visceral fat accumulation, hepatic steatosis, hyperleptinemia, hyperinsulinemia, and glucose intolerance. Hypertrophy of adipocytes, high levels of adipogenic regulator genes, such as SREBP1 and PPARγ, infiltration of macrophages, and the presence of CL structures were apparent in polη ^-/- mice.

Comparisons between healthy and pol η-deficient mice showed that polη ^-/- mice had higher levels of DNA damage and greater DDR, due to upregulation and phosphorylation of ATM, H2AX, p21, and p53, as well as upregulation of NF-κB and PARP-1 (Chen et al., 2015). Further, polη ^-/- mice also displayed increased DSBs. It was also found that polη ^-/- mice under a high-fat diet, which induces oxidative stress, showed a DNA-damage mediated senescence. Besides, treatment with a p53 inhibitor, pifithrin-α (PFT-α), reduced adipocyte senescence and attenuated the metabolic abnormalities. (Chen et al., 2015). On the contrary, DNA damage attenuation induced by N-acetylcysteine (NAC) or metformin antioxidants ameliorated cellular senescence and metabolic abnormalities. These results indicate that high levels of DNA damage are responsible for promoting adipocyte senescence, playing a crucial role in the development of obesity and IR (Chen et al., 2015). These data revealed the involvement of the DNA lesion bypass polymerase Pol η to protect against metabolic comorbidities.

The role of ATM

Ataxia-telangiectasia was first described in 1941 by Madam Louis-Bar as a disease characterized by progressive cerebellar ataxia followed by oculocutaneous telangiectasia. In 1957, Boder and Sedgwick reported the disease in seven patients, pointing to a family tendency and frequent pulmonary infection as less marked characteristics of the disease. In the same year, Wells and Shy founded an association between subcutaneous telangiectasia with progressive familial choreoathetosis. The disease caused a significant disorder in the central nervous system, which was initially overshadowed by pulmonary infections (Silberpfennig et al., 1941). Furthermore, ataxia-telangiectasia subjects display DM and IR (Bar et al., 1978; Blevins and Gebhart, 1996; Morio et al., 2009).

The ataxia-telangiectasia mutated (ATM) gene encodes to the ATM protein, a kinase of 350 kDa that plays a crucial role in DNA repair and is necessary for genomic homeostasis maintenance (Mercer et al., 2010). DSBs activate ATM, which phosphorylates its substrates (or targets) downstream, promoting DNA repair. The main ATM targets are H2AX, cycle cell checkpoints kinases Chk-1 and Chk-2, and the p53 tumoral suppressor gene (Mercer et al., 2010; Takagi et al., 2015). Although ATM is better characterized as a DDR gene, recent studies point out that defective ATM causes atherosclerosis and metabolic abnormalities. Using an apolipoprotein/ATM heterozygous (Atm ^+/- /ApoE^-/- ) mice, Mercer and co-workers revealed that Atm ^+/- /ApoE^-/- mice displayed accelerated atherosclerosis and multiple phenotypes of metabolic syndrome (Mercer et al., 2010). Further, Atm ^+/- mice were fat, hypertensive, macrophage infiltration, and showed hyperlipidemia under HFD. Fat accumulation and macrophage infiltration were also verified in Atm+/-/ApoE-/- mice. VSMCs from Atm ^+/- mice showed higher DNA fragmentation induced by the prooxidant t-BHP, higher levels of p-ATM and γ-H2AX relative to Atm ^+/+ mice, and presented a delayed activation of Chk-2 and p53, but not Chk-1 (Mercer et al., 2010). Furthermore, increased levels of ROS and mtDNA damage in Atm ^+/- mice were found.

Taken together, Mercer and co-workers observed that ATM haploinsufficiency results in DNA damage in cells that compose atherosclerotic plaques, in addition to accelerating atherosclerosis in vivo, and inducing several features of metabolic syndrome and mitochondrial dysfunction (Mercer et al., 2010). Therefore, defective ATM or its haploinsufficiency causes DNA damage, speeds up atherosclerosis and metabolic syndrome features, and may cause failure in DNA repair and p53 activation, resulting in the reduction of apoptosis and cycle cell interruption (Mercer et al., 2010).

CCAAT/enhancer binding protein α (C/EBPα) and PPARγ are considered the central regulator for adipocyte differentiation. When PPARγ is activated by an agonist in fibroblasts, a complete differentiation program is stimulated, leading to morphological changes, accumulation of lipids, and the expression of almost all characteristic genes of adipocytes (Rosen and Spiegelman, 2000). Another study revealed that ATM is activated during adipogenesis, besides DNA damage and insulin stimulation, and controls this process via transcriptional regulation of C/EBPα and/or PPARγ, which are required for a complete adipocyte maturation (Takagi et al., 2015). Neither lipid accumulation nor adipocyte differentiation occurred in embryonic fibroblasts of Atm ^-/- knockout mice since there was a defective induction of C/EBPα and PPARγ ATM-dependent expression (Takagi et al., 2015). Besides, it was observed that Atm ^-/- mice were insulin resistant, presented lower levels of adiponectin and leptin, had less subcutaneous and interscapular adipose tissue, increased visceral fat level (similar to metabolic syndrome), and glucose intolerance when compared to normal Atm ^+/+ mice (Takagi et al., 2015). Finally, it is worth mentioning the importance of adipose tissue for glucose homeostasis, considering that adipokines such as adiponectin, leptin, visfatin, and omentin increase insulin sensitivity, while hypertrophic adipocytes secrete resistin and Tumor Necrosis Factor-alpha (TNFα), which decrease sensitivity to insulin (Rosen and Spiegelman, 2006). Therefore, ATM deficiency leads to impaired adipocyte differentiation, which impairs adipokine secretion, resulting in IR and glucose intolerance (Takagi et al., 2015). These data revealed the ATM in the regulation of fat metabolism. However, the contribution of DNA damage accumulation and repair in Atm ^-/- mice remains to be determined.

Interactome analysis of DNA repair- and lipodystrophy-related Genes

To better clarify the interplay between the altered DNA repair pathways reviewed here and the lipodystrophies’ cell models associated with these DNA repair changes, we performed some systems biology analysis. The interactions of the main proteins described in this review were analyzed using STRING database (Szklarczyk et al., 2017), Cytoscape desktop application (Shannon et al., 2003) and its plugins: Molecular Complex Detection (MCODE) (Bader and Hogue, 2003), CentiScaPe (Scardoni et al., 2009), Biological Networks Gene Ontology (BiNGO) (Maere et al., 2005), and iRegulon (Heberle et al., 2015), and InteractiVenn web tool (Janky et al., 2014). The network containing 49 proteins was firstly built using STRING, which collects and integrates physical (direct) and functional (indirect) interactions. Later, the network was analyzed using Cytoscape. CentiScaPe was used to identify centrality parameters, determining the network nodes that are experimentally and topologically relevant. The protein-protein interactions (PPI) from the network revealed 676 interactions between DNA repair and lipodystrophic proteins (Figure 3A). Two protein clusters (densely connected regions) were detected by MCODE: one cluster had 42 nodes and 580 interactions, and the gene ontology (GO) determined by BiNGO was DNA metabolic process (Figure 3B). The second cluster had 30 genes and 258 interactions, and the BiNGO-determined GO was fat cell differentiation (Figure 3C). CentiScaPe analysis showed that the most dynamic nodes of the network, referred to as hub-bottlenecks (in blue), include: LMNA, WRN, TP53, ATM, PARP1, PPARG, CEBPA, CDK2, SREBF1, and IGF1. InteractiVenn analysis revealed that 23 genes from the network are common to Cluster 1 and Cluster 2, ratifying the interplay of proteins from DNA repair and adipogenesis (Figure 4A). It is important to notice that since the STRING network was used as an input to Cytoscape, some experimental data reviewed here were not shown in STRING and, consequently, they were not depicted in the Cytoscape network, such as PARP1 with CEBPB, BSCL2 with OGG1, APEX1, and NFE2L2. However, even without these data, the network had a significant number of PPI. To scrutinize the regulators of the network, iRegulon was used to find the main transcription factors (TFs) regulating the genes of the network. The TFs controlling cluster 1 (DNA metabolic process) were: FOXM1, NF-YA, SIN3A, and E2F4 (Figure 4B). The role of FOXM1 in DNA repair, cell proliferation, and tissue homeostasis was previously described in different works (Tan et al., 2007; Kwok et al., 2010; Millour et al., 2011; Zhang et al., 2012; Monteiro et al., 2013; Khongkow et al., 2014; Zona et al., 2014). NF-YA role in DNA damage/repair was also verified (Jin et al., 2001; Lee et al., 2004; Lin et al., 2014). Besides, SIN3A is associated with genomic integrity, and DNA damage (McDonel et al., 2012), and the role of E2F4 in cell cycle progression was also shown (Ren et al., 2002). Furthermore, the TFs that regulate cluster 2 (fat cell differentiation) were: CEBPB, ATF4, JUN, and POLR2A (Figure 4C). The role of these TFs in adipogenesis was previously shown (Yu et al., 2014; Guo et al., 2015; Lee et al., 2016; Bradford et al., 2019; Ahmed et al., 2019; Ambele et al., 2020; Bléher et al., 2020).

Figure 3 -
Network comprising the DNA repair- and lipodystrophy- related genes reviewed in this paper. A) PPI network of 49 genes showed high connectivity (676 interactions) between genes involved with DNA repair and adipose tissue. The STRING parameters for the Homo sapiens were: Experiments; Database; Neighborhood; and Textmining. The minimum required interaction score was: medium confidence (0.400). Ten hub-bottlenecks (in blue) were depicted by CentiScaPe CytoScape plug-in: LMNA, WRN, TP53, ATM, PARP1, PPARG, CEBPA, CDK2, SREBF1, and IGF1. Two clusters of the main network were depicted by MCODE CytoScape plug-in, and their Gene Ontology (GO) was obtained by BiNGO CytoScape plug-in. Cluster 1 (B) was composed of 42 genes and was associated with the DNA metabolic process, while cluster 2 (C) was formed by 30 genes and is related to fat cell differentiation.

Figure 4 -
Common and specific genes of cluster 1 (DNA metabolic process) and cluster 2 (fat cell differentiation) and their main transcription factors (TFs). A) InteractiVenn showed that 23 genes from the network are common to cluster 1 (in orange) and cluster 2 (in green), ratifying the crosstalk between proteins first described to have functions associated with DNA repair or adipogenesis. B) The main TFs (in green) regulating genes (in pink) from cluster 1 include: FOXM1, NF-YA, SIN3A, and E2F4. C) The main TFs that regulate genes (in pink) from cluster 2 were: CEBPB, POLR2A, ATF4, and JUN. The main TFs (in green) that regulate genes of both clusters were found using the iRegulon CytoScape plug-in.

Data reviewed here and the interactomes shown in Figures 3 and 4 reveal a vigorous connection between DNA repair and adipose tissue-related genes. However, how this PPI affects the functions of these genes in the context of adipocyte differentiation has yet to be investigated. Further, the role of the abovementioned TFs in the regulation of this PPI remains to be elucidated. Therefore, lipodystrophies can be a useful model for studying the mechanisms that link genome instability, metabolic dysregulation, and aging.

Concluding remarks and future directions

Over recent years, advancements in our understanding concerning the genetics of congenital lipodystrophies led to a better knowledge of the onset and progression of these rare diseases. This review highlighted several findings showing the interplay between genes associated with DNA repair and adipogenesis. Based on the many results reviewed here, we concluded that the maintenance of genomic integrity and an effective DNA repair contribute to adipose tissue homeostasis. Therefore, the treatment strategies of congenital lipodystrophies should focus on the elimination/reduction of DNA damage accumulation, as well as on antioxidant therapies.

Furthermore, some questions require more investigation. What is the link between genome stability and metabolism? How does DNA repair deficiency result in several forms of progeroid syndromes with lipodystrophy? How do lipodystrophies caused by pathogenic variants in adipose tissue-related genes result in DNA repair activation? To respond to these questions, it is crucial to scrutinize the DNA repair contributions in different adipose tissue depots obtained from adipose tissue-proficient and lipodystrophic cellular models.

Acknowledgements

This work was financially supported through grants from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Brazil. We would like to apologize in case we have missed any relevant studies in this review. We would like to acknowledge the website SMART - https://smart.servier.com/ (Les Laboratoires Servier) for providing us with some parts of our illustrations.

References

• Afonso P, Auclair M, Boccara F, Vantyghem MC, Katlama C, Capeau J, Vigouroux C and Caron-Debarle M (2016) LMNA mutations resulting in lipodystrophy and HIV protease inhibitors trigger vascular smooth muscle cell senescence and calcification: Role of ZMPSTE24 downregulation. Atherosclerosis 245:200-211.
• Agarwal AK, Arioglu E, De Almeida S, Akkoc N, Taylor SI, Bowcock AM, Barnes RI and Garg A (2002) AGPAT2 is mutated in congenital generalized lipodystrophy linked to chromosome 9q34. Nat Genet 31:21-23.
• Agarwal AK and Garg A (2002) A novel heterozygous mutation in peroxisome proliferator-activated receptor-gamma gene in a patient with familial partial lipodystrophy. J Clin Endocrinol Metab 87:408-408.
• Agarwal AK and Garg A (2003) Congenital generalized lipodystrophy: significance of triglyceride biosynthetic pathways. Trends Endocrinol Metab 14:214-221.
• Agarwal AK and Garg A (2006) Genetic disorders of adipose tissue development, differentiation, and death. Annu Rev Genomics Hum Genet 7:175-199.
• Agarwal AK, Fryns JP, Auchus RJ and Garg A (2003a) Zinc metalloproteinase, ZMPSTE24, is mutated in mandibuloacral dysplasia. Hum Mol Genet 12:1995-2001.
• Agarwal AK, Simha V, Oral EA, Moran SA, Gorden P, O’Rahilly S, Zaidi Z, Gurakan F, Arslanian SA, Klar A et al (2003b) Phenotypic and genetic heterogeneity in congenital generalized lipodystrophy. J Clin Endocrinol Metab 88:4840-4847.
• Agarwal AK, Zhou XJ, Hall RK, Nicholls K, Bankier A, Van Esch H, Fryns JP and Garg A (2006) Focal segmental glomerulosclerosis in patients with mandibuloacral dysplasia owing to ZMPSTE24 deficiency. J Investig Med 54:208-213.
• Ahmad Z, Zackai E, Medne L and Garg A (2010) Early onset mandibuloacral dysplasia due to compound heterozygous mutations in ZMPSTE24. Am J Med Genet A 152A:2703-2710.
• Ahmed M, Lai TH, Hwang JS, Zada S, Pham TM and Kim DR (2019) Transcriptional regulation of autophagy genes via stage-specific activation of CEBPB and PPARG during adipogenesis: A systematic study using public gene expression and transcription factor binding datasets. Cells8:1321.
• Ajluni N, Meral R, Neidert AH, Brady GF, Buras E, McKenna B, DiPaola F, Chenevert TL, Horowitz JF, Buggs-Saxton C et al (2017) Spectrum of disease associated with partial lipodystrophy: lessons from a trial cohort. Clin Endocrinol (Oxf) 86:698-707.
• Albert JS, Yerges-Armstrong LM, Horenstein RB, Pollin TI, Sreenivasan UT, Chai S, Blaner WS, Snitker S, O’Connell JR, Gong D-W et al (2014) Null mutation in hormone-sensitive lipase gene and risk of type 2 diabetes. N Engl J Med 370:2307-2315.
• Ambele MA, Dhanraj P, Giles R and Pepper MS (2020) Adipogenesis: A complex interplay of multiple molecular determinants and pathways. Int J Mol Sci 21:4283.
• Antuna-Puente B, Boutet E, Vigouroux C, Lascols O, Slama L, Caron-Debarle M, Khallouf E, Lévy-Marchal C, Capeau J, Bastard JP et al (2010) Higher adiponectin levels in patients with Berardinelli-Seip congenital lipodystrophy due to seipin as compared with 1-acylglycerol-3-phosphate-O- acyltransferase-2 deficiency. J Clin Endocrinol Metab 95:1463-1468.
• Araújo-Vilar D and Santini F (2019) Diagnosis and treatment of lipodystrophy: A step-by-step approach. J Endocrinol Invest 42:61-73.
• Araújo de Melo Campos JT, Dantas de Medeiros JL, Cardoso de Melo ME, Alvares da Silva M, Oliveira de Sena M, Sales Craveiro Sarmento A, Fassarella Agnez Lima L, de Freitas Fregonezi GA and Gomes Lima J (2021) Endoplasmic reticulum stress and muscle dysfunction in congenital lipodystrophies. Biochim Biophys Acta Mol Basis Dis 1867:166120.
• Azmanov DN, Siira SJ, Chamova T, Kaprelyan A, Guergueltcheva V, Shearwood AMJ, Liu G, Morar B, Rackham O, Bynevelt M et al (2016) Transcriptome-wide effects of a POLR3A gene mutation in patients with an unusual phenotype of striatal involvement. Hum Mol Genet 25:4302-4314.
• Bader GD and Hogue CWV (2003) An automated method for finding molecular complexes in large protein interaction networks. BMC Bioinformatics 4:1-27.
• Badman MK and Flier JS (2007) The adipocyte as an active participant in energy balance and metabolism. Gastroenterology 132:2103-2115.
• Báez-Becerra CT, Valencia-Rincón E, Velásquez-Méndez K, Ramírez-Suárez NJ, Guevara C, Sandoval-Hernandez A, Arboleda-Bustos CE, Olivos-Cisneros L, Gutiérrez-Ospina G, Arboleda H et al (2020) Nucleolar disruption, activation of P53 and premature senescence in POLR3A-mutated Wiedemann-Rautenstrauch syndrome fibroblasts. Mech Ageing Dev 192:111360.
• Balaban RS, Nemoto S and Finkel T (2005) Mitochondria, oxidants, and aging. Cell 120:483-495.
• Bar RS, Levis WR, Rechler MM, Harrison LC, Siebert C, Podskalny J, Roth J and Muggeo M (1978) Extreme insulin resistance in ataxia telangiectasia: Defect in affinity of insulin receptors. N Engl J Med 298:1164-1171.
• Barroso I, Gurnell M, Crowley VEF, Agostini M, Schwabe JW, Soos MA, Maslen GL, Williams TDM, Lewis H, Schafer AJ et al (1999) Dominant negative mutations in human PPARγ associated with severe insulin resistance, diabetes mellitus and hypertension. Nature 402:880-883.
• Bauer NC, Corbett AH and Doetsch PW (2015) The current state of eukaryotic DNA base damage and repair. Nucleic Acids Res43:10083-10101.
• Bergo MO, Gavino B, Ross J, Schmidt WK, Hong C, Kendall L V., Mohr A, Meta M, Genant H, Jiang Y et al (2002) Zmpste24 deficiency in mice causes spontaneous bone fractures, muscle weakness, and a prelamin A processing defect. Proc Natl Acad Sci U S A 99:13049-13054.
• Bertrand AT, Chikhaoui K, Yaou R Ben and Bonne G (2011) Clinical and genetic heterogeneity in laminopathies. Biochem Soc Trans39:1687-1692.
• Bhattacharyya A, Chattopadhyay R, Mitra S and Crowe SE (2014) Oxidative stress: An essential factor in the pathogenesis of gastrointestinal mucosal diseases. Physiol Rev 94:329-354.
• Bidault G, Garcia M, Vantyghem MC, Ducluzeau PH, Morichon R, Thiyagarajah K, Moritz S, Capeau J, Vigouroux C and Béréziat V (2013) Lipodystrophy-linked LMNA p.R482W mutation induces clinical early atherosclerosis and in vitro endothelial dysfunction. Arterioscler Thromb Vasc Biol 33:2162-2171.
• Bidault G, Garcia M, Capeau J, Morichon R, Vigouroux C and Béréziat V (2020) Progerin expression induces inflammation, oxidative stress and senescence in human coronary endothelial cells. Cells 9:1201.
• Bléher M, Meshko B, Cacciapuoti I, Gergondey R, Kovacs Y, Duprez D, L’Honoré A and Havis E (2020) Egr1 loss-of-function promotes beige adipocyte differentiation and activation specifically in inguinal subcutaneous white adipose tissue. Sci Rep 10:15842.
• Blevins LS and Gebhart SSP (1996) Insulin-resistant diabetes mellitus in a black woman with ataxia-telangiectasia. South Med J 89:619-621.
• Bloom D (1954) Congenital telangiectatic erythema resembling lupus erythematosus in dwarfs: Probably a syndrome entity. AMA Am J Dis Child 88:754-758.
• Bolderson E, Burgess JT, Li J, Gandhi NS, Boucher D, Croft L V., Beard S, Plowman JJ, Suraweera A, Adams MN et al (2019) Barrier-to-autointegration factor 1 (Banf1) regulates poly [ADP-ribose] polymerase 1 (PARP1) activity following oxidative DNA damage. Nat Commun 10:5501.
• Brace LE, Vose SC, Vargas DF, Zhao S, Wang XP and Mitchell JR (2013) Lifespan extension by dietary intervention in a mouse model of Cockayne syndrome uncouples early postnatal development from segmental progeria. Aging Cell 12:1144-1147.
• Brace LE, Vose SC, Stanya K, Gathungu RM, Marur VR, Longchamp A, Treviño-Villarreal H, Mejia P, Vargas D, Inouye K et al (2016) Increased oxidative phosphorylation in response to acute and chronic DNA damage. NPJ Aging Mech Dis 2:16022.
• Bradford ST, Nair SS, Statham AL, van Dijk SJ, Peters TJ, Anwar F, French HJ, von Martels JZH, Sutcliffe B, Maddugoda MP et al (2019) Methylome and transcriptome maps of human visceral and subcutaneous adipocytes reveal key epigenetic differences at developmental genes. Sci Rep9:9511.
• Broers JLV, Ramaekers FCS, Bonne G, Ben Yaou R and Hutchison CJ (2006) Nuclear lamins: Laminopathies and their role in premature ageing. Physiol Rev 86:967-1008.
• Brown RJ, Araujo-Vilar D, Cheung PT, Dunger D, Garg A, Jack M, Mungai L, Oral EA, Patni N, Rother KI et al (2016) The diagnosis and management of lipodystrophy syndromes: A multi-society practice guideline. J Clin Endocrinol Metab 101:4500-4511.
• Cabanillas R, Cadiñanos J, Villameytide JAF, Pérez M, Longo J, Richard JM, Álvarez R, Durán NS, Illán R, González DJ et al (2011) Néstor-Guillermo progeria syndrome: a novel premature aging condition with early onset and chronic development caused by BANF1 mutations. Am J Med Genet 155A:2617-2625.
• Cadet J, Douki T, Gasparutto D and Ravanat JL (2003) Oxidative damage to DNA: Formation, measurement and biochemical features. Mutat Res 531:5-23.
• Cao H, Alston L, Ruschman J and Hegele RA (2008) Heterozygous CAV1 frameshift mutations (MIM 601047) in patients with atypical partial lipodystrophy and hypertriglyceridemia. Lipids Health Dis 7:3.
• Capel E, Vatier C, Cervera P, Stojkovic T, Disse E, Cottereau AS, Auclair M, Verpont MC, Mosbah H, Gourdy P et al (2018) MFN2-associated lipomatosis: Clinical spectrum and impact on adipose tissue. J Clin Lipidol 12:1420-1435.
• Caron M, Auclair M, Donadille B, Béréziat V, Guerci B, Laville M, Narbonne H, Bodemer C, Lascols O, Capeau J et al (2007) Human lipodystrophies linked to mutations in A-type lamins and to HIV protease inhibitor therapy are both associated with prelamin A accumulation, oxidative stress and premature cellular senescence. Cell Death Differ 14:1759-1767.
• Carrero D, Soria-Valles C and López-Otín C (2016) Hallmarks of progeroid syndromes: Lessons from mice and reprogrammed cells. Dis Model Mech 9:719-735.
• Cenni V, D’Apice MR, Garagnani P, Columbaro M, Novelli G, Franceschi C and Lattanzi G (2018) Mandibuloacral dysplasia: A premature ageing disease with aspects of physiological ageing. Ageing Res Rev 42:1-13.
• Chan D, McIntyre AD, Hegele RA and Don-Wauchope AC (2016) Familial partial lipodystrophy presenting as metabolic syndrome. J Clin Lipidol 10:1488-1491.
• Chen YW, Harris RA, Hatahet Z and Chou KM (2015) Ablation of XP-V gene causes adipose tissue senescence and metabolic abnormalities. Proc Natl Acad Sci U S A 112:E4556-E4564.
• Choe SS, Huh JY, Hwang IJ, Kim JI and Kim JB (2016) Adipose tissue remodeling: Its role in energy metabolism and metabolic disorders. Front Endocrinol (Lausanne)7:30.
• Cleaver JE (1968) Defective repair replication of DNA in Xeroderma Pigmentosum. Nature 218:652-656.
• Cockayne EA (1936) Dwarfism with retinal atrophy and deafness. Arch Dis Child 11:1-8.
• Combot Y, Salo VT, Chadeuf G, Hölttä M, Ven K, Pulli I, Ducheix S, Pecqueur C, Renoult O, Lak B et al (2022) Seipin localizes at endoplasmic-reticulum-mitochondria contact sites to control mitochondrial calcium import and metabolism in adipocytes. Cell Rep 38:110213.
• Craveiro Sarmento AS, Ferreira LC, Lima JG, de Azevedo Medeiros LB, Barbosa Cunha PT, Agnez-Lima LF, Galvão Ururahy MA, de Melo Campos JTA, de Lima JG, de Azevedo Medeiros LB et al (2019) The worldwide mutational landscape of Berardinelli-Seip congenital lipodystrophy. Mutat Res Rev Mutat Res781:30-52.
• Craveiro Sarmento AS, Gomes Lima J, de Souza Timoteo AR, Galvão Ururahy MA, Antunes de Araújo A, Carvalho Vasconcelos R, Cândido Dantas VK, Fassarella Agnez-Lima L and Araújo de Melo Campos JT (2020) Changes in redox and endoplasmic reticulum homeostasis are related to congenital generalized lipodystrophy type 2. Biochim Biophys Acta Mol Cell Biol Lipids1865:158610.
• Crocker HR (1884) Three cases of Xeroderma Pigmentosum (Kaposi) or Atrophoderma Pigmentosum. Med Chir Trans 67:169-188.
• Cunningham VJ, D’Apice MR, Licata N, Novelli G and Cundy T (2010) Skeletal phenotype of mandibuloacral dysplasia associated with mutations in ZMPSTE24. Bone 47:591-597.
• D’Errico M, Parlanti E, Teson M, De Jesus BMB, Degan P, Calcagnile A, Jaruga P, Bjørås M, Crescenzi M, Pedrini AM et al (2006) New functions of XPC in the protection of human skin cells from oxidative damage. EMBO J 25:4305-4315.
• Dantas de Medeiros JL, Carneiro Bezerra B, Anderson Brito de Araújo T, Sales Craveiro Sarmento A, de Azevedo Medeiros LB, Gualdi LP, Luna Cruz MDS, Teixeira Xavier Nobre T, Lima JG and Araújo de Melo Campos JT (2018) Impairment of respiratory muscle strength in Berardinelli-Seip congenital lipodystrophy subjects. Respir Res 19:173.
• de Azevedo Medeiros LB, Cândido Dantas VK, Craveiro Sarmento AS, Agnez-Lima LF, Meireles AL, Xavier Nobre TT, de Lima JG and de Melo Campos JTA (2017) High prevalence of Berardinelli-Seip congenital lipodystrophy in Rio Grande do Norte state, Northeast Brazil. Diabetol Metab Syndr 9:80.
• de Melo JTA, de Souza Timoteo AR, Lajus TBP, Brandão JA, de Souza-Pinto NC, Menck CFM, Campalans A, Radicella JP, Vessoni AT, Muotri AR et al (2016) XPC deficiency is related to APE1 and OGG1 expression and function. Mutat Res 784-785:25-33.
• De Sandre-Giovannoli A, Bernard R, Cau P, Navarro C, Amiel J, Boccaccio I, Lyonnet S, Stewart CL, Munnich A, Le Merrer M et al (2003) Lamin A truncation in Hutchinson-Gilford progeria. Science 300:2055.
• Debray F-G, Baguette C, Colinet S, Van Maldergem L and Verellen-Dumouin C (2013) Early infantile cardiomyopathy and liver disease: A multisystemic disorder caused by congenital lipodystrophy. Mol Genet Metab 109:227-229.
• Devalaraja-Narashimha K and Padanilam BJ (2010) PARP1 deficiency exacerbates diet-induced obesity in mice. J Endocrinol 205:243-252.
• Di Masi A, D’Apice MR, Ricordy R, Tanzarella C and Novelli G (2008) The R527H mutation in LMNA gene causes an increased sensitivity to ionizing radiation. Cell Cycle 7:2030-2037.
• Dianov G, Bischoff C, Sunesen M and Bohr VA (1999) Repair of 8-oxoguanine in DNA is deficient in Cockayne syndrome group B cells. Nucleic Acids Res 27:1365-1368.
• Diaz A, Vogiatzi MG, Sanz MM and German J (2006) Evaluation of short stature, carbohydrate metabolism and other endocrinopathies in Bloom’s syndrome. Horm Res 66:111-117.
• Dunnigan MG, Cochrane MA, Kelly A and Scott JW (1974) Familial lipoatrophic diabetes with dominant transmission. A New syndrome. Q J Med 43:33-48.
• Ellis NA and German J (1996) Molecular genetics of Bloom’s syndrome. Hum Mol Genet 5:1457-1463.
• Elouej S, Beleza-Meireles A, Caswell R, Colclough K, Ellard S, Desvignes JP, Béroud C, Lévy N, Mohammed S and De Sandre-Giovannoli A (2017) Exome sequencing reveals a de novo POLD1 mutation causing phenotypic variability in mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome (MDPL). Metabolism71:213-225.
• Epstein CJ, Martin GM, Sohultz AL and Motulsky AG (1966) Werner’s syndrome a review of its symptomatology, natural history, pathologic features, genetics and relationship to the natural aging process. Medicine (Baltimore) 45:177-221.
• Eriksson M, Brown WT, Gordon LB, Glynn MW, Singer J, Scott L, Erdos MR, Robbins CM, Moses TY, Berglund P et al (2003) Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Nature 423:293-298.
• Eun HK, Park JY, Park HS, Min JJ, Je WR, Kim M, Sun YK, Kim MS, Kim SW, In SP et al (2007) Essential role of mitochondrial function in adiponectin synthesis in adipocytes. Diabetes 56:2973-2981.
• Evans MD, Dizdaroglu M and Cooke MS (2004) Oxidative DNA damage and disease: induction, repair and significance. Mutat Res 567:1-61.
• Faria CA, Moraes RS, Sobral-Filho DC, Rego AG, Baracho MFP, Egito EST and Brandão-Neto J (2009) Autonomic modulation in patients with congenital generalized lipodystrophy (Berardinelli-Seip syndrome). Europace 11:763-769.
• Fernández-Pombo A, Sánchez-Iglesias S, Cobelo-Gómez S, Hermida-Ameijeiras Á and Araújo-Vilar D (2021) Familial partial lipodystrophy syndromes. Presse Med 50:104071.
• Fiorillo C, D’Apice MR, Trucco F, Murdocca M, Spitalieri P, Assereto S, Baratto S, Morcaldi G, Minetti C, Sangiuolo F et al (2018) Characterization of MDPL fibroblasts carrying the recurrent p.Ser605del mutation in POLD1 gene. DNA Cell Biol 37:1061-1067.
• Fouquerel E and Sobol RW (2014) ARTD1 (PARP1) activation and NAD+ in DNA repair and cell death. DNA Repair (Amst) 23:27-32.
• Fousteri M and Mullenders LHF (2008) Transcription-coupled nucleotide excision repair in mammalian cells: molecular mechanisms and biological effects. Cell Res 18:73-84.
• Freidenberg GR, Cutler DL, Jones MC, Hall B, Mier RJ, Culler F, Jones KL, Lozzio C and Kaufmann S (1992) Severe insulin resistance and diabetes mellitus in mandibuloacral dysplasia. Am J Dis Child 146:93-99.
• Gandotra S, Le Dour C, Bottomley W, Cervera P, Giral P, Reznik Y, Charpentier G, Auclair M, Delépine M, Barroso I et al (2011) Perilipin deficiency and autosomal dominant partial lipodystrophy. N Engl J Med 364:740-748.
• Garg A (2011) Lipodystrophies: Genetic and acquired body fat disorders. J Clin Endocrinol Metab 96:3313-3325.
• Garg A (2000) Lipodystrophies. Am J Med 108:143-152.
• Garg A and Agarwal AK (2009) Lipodystrophies: Disorders of adipose tissue biology. Biochim Biophys Acta 1791:507-513.
• Garg A, Fleckenstein JL, Peshock RM and Grundy SM (1992) Peculiar distribution of adipose tissue in patients with congenital generalized lipodystrophy. J Clin Endocrinol Metab 75:358-361.
• Garg A, Kircher M, del Campo M, Amato RS and Agarwal AK (2015) Whole exome sequencing identifies de novo heterozygous CAV1 mutations associated with a novel neonatal onset lipodystrophy syndrome. Am J Med Genet A 167A:1796-1806.
• Garg A, Vinaitheerthan M, Weatherall PT and Bowcock AM (2001) Phenotypic heterogeneity in patients with familial partial lipodystrophy (Dunnigan variety) related to the site of missense mutations in lamin A/C gene. J Clin Endocrinol Metab 86:59-65.
• Goh KJ, Chen JH, Rocha N and Semple RK (2020) Human pluripotent stem cell-based models suggest preadipocyte senescence as a possible cause of metabolic complications of Werner and Bloom Syndromes. Sci Rep 10:7490.
• Goldman RD, Shumaker DK, Erdos MR, Eriksson M, Goldman AE, Gordon LB, Gruenbaum Y, Khuon S, Mendez M, Varga R et al (2004) Accumulation of mutant lamin A causes progressive changes in nuclear architecture in Hutchinson-Gilford progeria syndrome. Proc Natl Acad Sci U S A 101:8963-8968.
• Gonzalo S and Kreienkamp R (2015) DNA repair defects and genome instability in Hutchinson-Gilford Progeria Syndrome. Curr Opin Cell Biol 34:75-83.
• Gonzalo S, Kreienkamp R and Askjaer P (2017) Hutchinson-Gilford progeria syndrome: A premature aging disease caused by LMNA gene mutations. Ageing Res Rev 33:18-29.
• Gordon LB, Rothman FG, López-Otín C and Misteli T (2014) Progeria: A paradigm for translational medicine. Cell 156:400-407.
• Goto M (1997) Hierarchical deterioration of body systems in Werner’s syndrome: implications for normal ageing. Mech Ageing Dev 98:239-254.
• Goto M, Ishikawa Y, Sugimoto M and Furuichi Y (2013) Werner syndrome: A changing pattern of clinical manifestations in Japan (1917~2008). Biosci Trends 7:13-22.
• Guo L, Li X and Tang QQ (2015) Transcriptional regulation of adipocyte differentiation: A central role for CCAAT/enhancer-binding protein (C/EBP) β. J Biol Chem 290:755-761.
• Hayashi YK, Matsuda C, Ogawa M, Goto K, Tominaga K, Mitsuhashi S, Park YE, Nonaka I, Hino-Fukuyo N, Haginoya K et al (2009) Human PTRF mutations cause secondary deficiency of caveolins resulting in muscular dystrophy with generalized lipodystrophy. J Clin Invest 119:2623-2633.
• Haye D, Dridi H, Levy J, Lambert V, Lambert M, Agha M, Adjimi F, Kohlhase J, Lipsker D and Verloes A (2016) Failure of ossification of the occipital bone in mandibuloacral dysplasia type B. Am J Med Genet A 170:2750-2755.
• Heberle H, Meirelles VG, da Silva FR, Telles GP and Minghim R (2015) InteractiVenn: A web-based tool for the analysis of sets through Venn diagrams. BMC Bioinformatics 16:169.
• Hegele RA, Cao H, Frankowski C, Mathews ST and Leff T (2002) PPARG F388L, a transactivation-deficient mutant, in familial partial lipodystrophy. Diabetes 51:3586-3590.
• Hickson ID (2003) RecQ helicases: Caretakers of the genome. Nat Rev Cancer 3:169-178.
• Hitzert MM, Van Der Crabben SN, Baldewsingh G, Van Amstel HKP, Van Den Wijngaard A, Van Ravenswaaij-Arts CMA and Zijlmans CWR (2019) Mandibuloacral dysplasia type B (MADB): A cohort of eight patients from Suriname with a homozygous founder mutation in ZMPSTE24 (FACE1), clinical diagnostic criteria and management guidelines. Orphanet J Rare Dis 14:294.
• Ho R and Hegele RA (2019) Complex effects of laminopathy mutations on nuclear structure and function. Clin Genet 95:199-209.
• Horn D and Robinson PN (2011) Progeroid facial features and lipodystrophy associated with a novel splice site mutation in the final intron of the FBN1 gene. Am J Med Genet A 155:721-724.
• Huang S, Lee L, Hanson NB, Lenaerts C, Hoehn H, Poot M, Rubin CD, Chen DF, Yang CC, Juch H et al (2006) The spectrum of WRN mutations in Werner syndrome patients. Hum Mutat 27:558-567.
• Hurtado-Bagès S, Knobloch G, Ladurner AG and Buschbeck M (2020) The taming of PARP1 and its impact on NAD+ metabolism. Mol Metab 38:100950.
• Hutchinson J (1886) Congenital absence of hair and mammary glands with atrophic condition of the skin and its appendages, in a boy whose mother had been almost wholly bald from alopecia areata from the age of six. Med Chir Trans 69:473-477.
• Item F and Konrad D (2012) Visceral fat and metabolic inflammation: The portal theory revisited. Obes Rev 13:30-39.
• Janky R, Verfaillie A, Imrichová H, Van de Sande B, Standaert L, Christiaens V, Hulselmans G, Herten K, Naval Sanchez M, Potier D et al (2014) IRegulon: From a gene list to a gene regulatory network using large motif and track collections. PLoS Comput Biol 10:e1003731.
• Jay AM, Conway RL, Thiffault I, Saunders C, Farrow E, Adams J and Toriello HV (2016) Neonatal progeriod syndrome associated with biallelic truncating variants in POLR3A. Am J Med Genet A 170:3343-3346.
• Jeggo PA, Pearl LH and Carr AM (2016) DNA repair, genome stability and cancer: A historical perspective. Nat Rev Cancer 16:35-42.
• Jin S, Fan F, Fan W, Zhao H, Tong T, Blanck P, Alomo I, Rajasekaran B and Zhan Q (2001) Transcription factors Oct-1 and NF-YA regulate the p53-independent induction of the GADD45 following DNA damage. Oncogene 20:2683-2690.
• Kamenisch Y, Fousteri M, Knoch J, von Thaler A-K, Fehrenbacher B, Kato H, Becker T, Dollé MET, Kuiper R, Majora M et al (2010) Proteins of nucleotide and base excision repair pathways interact in mitochondria to protect from loss of subcutaneous fat, a hallmark of aging. J Exp Med 207:379-390.
• Karakasilioti I, Kamileri I, Chatzinikolaou G, Kosteas T, Vergadi E, Robinson AR, Tsamardinos I, Rozgaja TA, Siakouli S, Tsatsanis C et al (2013) DNA damage triggers a chronic auto-inflammatory response leading to fat depletion in NER progeria. Cell Metab 18:403-415.
• Khongkow P, Karunarathna U, Khongkow M, Gong C, Gomes AR, Yagüe E, Monteiro LJ, Kongsema M, Zona S, Man EPS et al (2014) FOXM1 targets NBS1 to regulate DNA damage-induced senescence and epirubicin resistance. Oncogene 33:4144-4155.
• Kim CA, Delépine M, Boutet E, El Mourabit H, Le Lay S, Meier M, Nemani M, Bridel E, Leite CC, Bertola DR et al (2008) Association of a homozygous nonsense caveolin-1 mutation with Berardinelli-Seip congenital lipodystrophy. J Clin Endocrinol Metab 93:1129-1134.
• Kirkland JL, Tchkonia T, Pirtskhalava T, Han J and Karagiannides I (2002) Adipogenesis and aging: Does aging make fat go MAD? Exp Gerontol 37:757-767.
• Komakula SSB, Blaze B, Ye H, Dobrzyn A and Sampath H (2021) A novel role for the DNA repair enzyme 8-oxoguanine DNA glycosylase in adipogenesis. Int J Mol Sci 22:1152.
• Komakula SSB, Tumova J, Kumaraswamy D, Burchat N, Vartanian V, Ye H, Dobrzyn A, Lloyd RS and Sampath H (2018) The DNA repair protein OGG1 protects against obesity by altering mitochondrial energetics in white adipose tissue. Sci Rep 8:14886.
• Kraemer KH, Lee MM and Scotto J (1987) Xeroderma pigmentosum. Cutaneous, ocular, and neurologic abnormalities in 830 published cases. Arch Dermatol 123:241-250.
• Krasikova Y, Rechkunova N and Lavrik O (2021) Nucleotide excision repair: From molecular defects to neurological abnormalities. Int J Mol Sci 22:6220.
• Krokan HE and Bjørås M (2013) Base excision repair. Cold Spring Harb Perspect Biol 5:a012583.
• Kubben N, Zhang W, Wang L, Voss TC, Yang J, Qu J, Liu GH and Misteli T (2016) Repression of the antioxidant NRF2 pathway in premature aging. Cell 165:1361-1374.
• Kumar N, Moreno NC, Feltes BC, Menck CFM and Van Houten B (2020) Cooperation and interplay between base and nucleotide excision repair pathways: from DNA lesions to proteins. Genet Mol Biol 43:e20190104.
• Kwok JMM, Peck B, Monteiro LJ, Schwenen HDC, Millour J, Coombes RC, Myatt SS and Lam EWF (2010) FOXM1 confers acquired cisplatin resistance in breast cancer cells. Mol Cancer Res8:24-34.
• László A and Simon M (1986) Serum lipid and lipoprotein levels in premature ageing syndromes: Total lipodystrophy and Cockayne syndrome. Arch Gerontol Geriatr5:189-196.
• Lattanzi G, Ortolani M, Columbaro M, Prencipe S, Mattioli E, Lanzarini C, Maraldi NM, Cenni V, Garagnani P, Salvioli S et al (2014) 3are rapamycin targets that impact human longevity: A study in centenarians. J Cell Sci 127:147-157.
• Lauper JM, Krause A, Vaughan TL and Monnat RJ (2013) Spectrum and risk of neoplasia in Werner syndrome: A systematic review. PLoS One 8:e59709.
• Lazarte J and Hegele RA (2021) Lamin A/C missense variants: From discovery to functional validation. NPJ Genom Med 6:102.
• Lazarte J, Wang J, McIntyre AD and Hegele RA (2021) Prevalence of severe hypertriglyceridemia and pancreatitis in familial partial lipodystrophy type 2. J Clin Lipidol 15:653-657.
• Le Lay S, Magré J and Prieur X (2022) Not enough fat: Mouse models of inherited lipodystrophy. Front Endocrinol (Lausanne) 13:785819.
• Lee DS, Choi H, Han BS, Kim WK, Lee SC, Oh KJ and Bae KH (2016) C-Jun regulates adipocyte differentiation via the KLF15-mediated mode. Biochem Biophys Res Commun 469:552-558.
• Lee MR, Kim SH, Cho HJ, Lee KY, Moon AR, Jeong HG, Lee JS, Hyun JW, Chung MH and You HJ (2004) Transcription factors NF-YA regulate the induction of human OGG1 following DNA-alkylating agent methylmethane sulfonate (MMS) treatment. J Biol Chem 279:9857-9866.
• Les Laboratoires Servier SMART. In: Servier Med. ART. https://smart.servier.com/
  » https://smart.servier.com/
• Lessel D and Kubisch C (2019) Hereditary syndromes with signs of premature aging. Dtsch Arztebl Int 116:489-496.
• Lessel D, Vaz B, Halder S, Lockhart PJ, Marinovic-Terzic I, Lopez-Mosqueda J, Philipp M, Sim JCH, Smith KR, Oehler J et al (2014) Mutations in SPRTN cause early onset hepatocellular carcinoma, genomic instability and progeroid features. Nat Genet 46:1239-1244.
• Li F, Raczynska JE, Chen Z and Yu H (2019) Structural insight into DNA-dependent activation of human metalloprotease spartan. Cell Rep 26:3336-3346.e4.
• Li H, Yao W, Irwin MG, Wang T, Wang S, Zhang L and Xia Z (2015) Adiponectin ameliorates hyperglycemia-induced cardiac hypertrophy and dysfunction by concomitantly activating Nrf2 and Brg1. Free Radic Biol Med 84:311-321.
• Li L and Zou L (2005) Sensing, signaling, and responding to DNA damage: Organization of the checkpoint pathways in mammalian cells. J Cell Biochem 94:298-306.
• Lia D, Reyes A, de Melo Campos JTA, Piolot T, Baijer J, Radicella JP and Campalans A (2018) Mitochondrial maintenance under oxidative stress depends on mitochondrially localised α-OGG1. J Cell Sci 131:jcs213538.
• Lim K, Haider A, Adams C, Sleigh A and Savage DB (2021) Lipodistrophy: A paradigm for understanding the consequences of “overloading” adipose tissue. Physiol Rev 101:907-993.
• Lima JG, Nobrega LHC, De Lima NN, Do Nascimento Santos MG, Baracho MFP and Jeronimo SMB (2016) Clinical and laboratory data of a large series of patients with congenital generalized lipodystrophy. Diabetol Metab Syndr 8:23.
• Lima JG, Nobrega LHC, Lima NN, Santos MCF, Baracho MFP, Winzenrieth R, Bandeira F, Mendes-Aguiar CO, Freire Neto FP, Ferreira LC et al (2017) Normal bone density and trabecular bone score, but high serum sclerostin in congenital generalized lipodystrophy. Bone 101:21-25.
• Lima JG, Nobrega LHC, Lima NN, dos Santos MCF, Baracho M de FP, Bandeira F, Capistrano L, Freire Neto FP and Jeronimo SMB (2018a) Bone density in patients with Berardinelli-Seip congenital lipodystrophy is higher in trabecular sites and in type 2 patients. J Clin Densitom 21:61-67.
• Lima JG, Nobrega LHC, Lima NN, Dos Santos MCF, Silva PHD, Baracho M de FP, Lima DN, de Melo Campos JTA, Ferreira LC, Freire Neto FP et al (2018b) Causes of death in patients with Berardinelli-Seip congenital generalized lipodystrophy. PLoS One 13:e0199052.
• Limpose KL, Corbett AH and Doetsch PW (2017) BERing the burden of damage: pathway crosstalk and posttranslational modification of base excision repair proteins regulate DNA damage management. DNA Repair (Amst) 56:51-64.
• Lin YC, Chen YN, Lin KF, Wang FF, Chou TY and Chen MY (2014) Association of p21 with NF-YA suppresses the expression of Polo-like kinase 1 and prevents mitotic death in response to DNA damage. Cell Death Dis 5:e987.
• Liu B, Wang J, Chan KM, Tjia WM, Deng W, Guan X, Huang JD, Li KM, Chau PY, Chen DJ et al (2005) Genomic instability in laminopathy-based premature aging. Nat Med 11:780-785.
• Liu GH, Barkho BZ, Ruiz S, Diep D, Qu J, Yang SL, Panopoulos AD, Suzuki K, Kurian L, Walsh C et al (2011) Recapitulation of premature aging with iPSCs from Hutchinson-Gilford progeria syndrome. Nature 472:221-225.
• Liu Y, Rusinol A, Sinensky M, Wang Y and Zou Y (2006) DNA damage responses in progeroid syndromes arise from defective maturation of prelamin A. J Cell Sci 119:4644-4649.
• Liu Y, Wang Y, Rusinol AE, Sinensky MS, Liu J, Shell SM and Zou Y (2008) Involvement of xeroderma pigmentosum group A (XPA) in progeria arising from defective maturation of prelamin A. FASEB J 22:603-611.
• Liu Y, Drozdov I, Shroff R, Beltran LE and Shanahan CM (2013) Prelamin A accelerates vascular calcification via activation of the DNA damage response and senescence-associated secretory phenotype in vascular smooth muscle cells. Circ Res 112:e99-e109.
• Liu Z, Jin L, Yang JK, Wang B, Wu KKL, Hallenborg P, Xu A and Cheng KKY (2018) The dysfunctional MDM2-p53 axis in adipocytes contributes to aging-related metabolic complications by induction of lipodystrophy. Diabetes 67:2397-2409.
• Lopez-Mosqueda J, Maddi K, Prgomet S, Kalayil S, Marinovic-Terzic I, Terzic J and Dikic I (2016) SPRTN is a mammalian DNA-binding metalloprotease that resolves DNA-protein crosslinks. Elife 5:e21491.
• López-Otín C, Blasco MA, Partridge L, Serrano M and Kroemer G (2013) The hallmarks of aging. Cell 153:1194-1217.
• Luo X, Ryu KW, Kim DS, Nandu T, Medina CJ, Gupte R, Gibson BA, Soccio RE, Yu Y, Gupta RK et al (2017) PARP-1 controls the adipogenic transcriptional program by PARylating C/EBPβ and modulating its transcriptional activity. Mol Cell 65:260-271.
• Maere S, Heymans K and Kuiper M (2005) BiNGO: A Cytoscape plugin to assess overrepresentation of gene ontology categories in biological networks. Bioinformatics 21:3448-3449.
• Magré J, Delépine M, Khallouf E, Gedde-Dahl Jr T, Maldergem LV, Sobel E, Papp J, Meier M, Mégarbané A, Bachy A et al (2001) Identification of the gene altered in Berardinelli-Seip congenital lipodystrophy on chromosome 11q13. Nat Genet 28:365-370.
• Maldergem LV , Magré J , Khallouf TE, Gedde-Dahl Jr T, Delépine M , Trygstad O, Seemanova E, Stephenson T, Albott CS, Bonnici F et al (2002) Genotype-phenotype relationships in Berardinelli-Seip congenital lipodystrophy. J Med Genet 39:722-733.
• Marcelot A, Worman HJ and Zinn-Justin S (2020) Protein structural and mechanistic basis of progeroid laminopathies. FEBS J 288:2757-2772.
• Martin GM, Hisama FM and Oshima J (2021) Review of how genetic research on segmental progeroid syndromes has documented genomic instability as a hallmark of aging but let us now pursue antigeroid syndromes! J Gerontol A Biol Sci Med Sci 76:253-259.
• Maskey RS, Kim MS, Baker DJ, Childs B, Malureanu LA, Jeganathan KB, Machida Y, Van Deursen JM and Machida YJ (2014) Spartan deficiency causes genomic instability and progeroid phenotypes. Nat Commun 5:5744.
• Maskey RS, Flatten KS, Sieben CJ, Peterson KL, Baker DJ, Nam HJ, Kim MS, Smyrk TC, Kojima Y, Machida Y et al (2017) Spartan deficiency causes accumulation of Topoisomerase 1 cleavage complexes and tumorigenesis. Nucleic Acids Res 45:4564-4576.
• Masutani C, Araki M, Yamada A, Kusumoto R, Nogimori T, Maekawa T, Iwai S and Hanaoka F (1999) Xeroderma pigmentosum variant (XP-V) correcting protein from HeLa cells has a thymine dimer bypass DNA polymerase activity. EMBO J 18:3491-3501.
• Maynard S, Keijzers G, Akbari M, Ezra MB, Hall A, Morevati M, Scheibye-Knudsen M, Gonzalo S, Bartek J and Bohr VA (2019) Lamin A/C promotes DNA base excision repair. Nucleic Acids Res 47:11709-11728.
• McDonel P, Demmers J, Tan DWM, Watt F and Hendrich BD (2012) Sin3a is essential for the genome integrity and viability of pluripotent cells. Dev Biol 363:62-73.
• McKusick VA (2005) The Gordon Wilson lecture: the clinical legacy of Jonathan Hutchinson (1828-1913): Syndromology and sysmorphology meet genomics. Trans Am Clin Climatol Assoc 116:15-38.
• Menck CFM and Munford V (2014) DNA repair diseases: what do they tell us about cancer and aging? Genet Mol Biol 37:220-233.
• Mercer JR, Cheng KK, Figg N, Gorenne I, Mahmoudi M, Griffin J, Vidal-Puig A, Logan A, Murphy MP and Bennett M (2010) DNA damage links mitochondrial dysfunction to atherosclerosis and the metabolic syndrome. Circ Res 107:1021-1031.
• Millour J, Olano N, Horimoto Y, Monteiro LJ, Langer JK, Aligue R, Hajji N and Lam EWF (2011) ATM and p53 regulate FOXM1 expression via E2F in breast cancer epirubicin treatment and resistance. Mol Cancer Ther 10:1046-1053.
• Miyoshi Y, Akagi M, Agarwal AK, Namba N, Kato-Nishimura K, Mohri I, Yamagata M, Nakajima S, Mushiake S, Shima M et al (2008) Severe mandibuloacral dysplasia caused by novel compound heterozygous ZMPSTE24 mutations in two Japanese siblings. Clin Genet 73:535-544.
• Monteiro LJ, Khongkow P, Kongsema M, Morris JR, Man C, Weekes D, Koo CY, Gomes AR, Pinto PH, Varghese V et al (2013) The Forkhead Box M1 protein regulates BRIP1 expression and DNA damage repair in epirubicin treatment. Oncogene 32:4634-4645.
• Morio T, Takahashi N, Watanabe F, Honda F, Sato M, Takagi M, Imadome KI, Miyawaki T, Delia D, Nakamura K et al (2009) Phenotypic variations between affected siblings with ataxia-telangiectasia: Ataxia-telangiectasia in Japan. Int J Hematol90:455-462.
• Murdocca M, Spitalieri P, Masi CD, Udroiu I, Marinaccio J, Sanchez M, Talarico RV, Fiorillo C, D’Adamo M, Sbraccia P et al (2021) Functional analysis of POLD1 p.ser605del variant: the aging phenotype of MDPL syndrome is associated with an impaired DNA repair capacity. Aging (Albany NY) 13:4926-4945.
• Nance MA and Berry SA (1992) Cockayne syndrome: Review of 140 cases. Am J Med Genet 42:68-84.
• Niedernhofer LJ, Garinis GA, Raams A, Lalai AS, Robinson AR, Appeldoorn E, Odijk H, Oostendorp R, Ahmad A, Van Leeuwen W et al (2006) A new progeroid syndrome reveals that genotoxic stress suppresses the somatotroph axis. Nature 444:1038-1043.
• Niedernhofer LJ, Gurkar AU, Wang Y, Vijg J, Hoeijmakers JHJ and Robbins PD (2018) Nuclear genomic instability and aging. Annu Rev Biochem 87:295-322.
• Noren Hooten N, Kompaniez K, Barnes J, Lohani A and Evans MK (2011) Poly(ADP-ribose) polymerase 1 (PARP-1) binds to 8-oxoguanine-DNA glycosylase (OGG1). J Biol Chem 286:44679-44690.
• Novelli G, Muchir A, Sangiuolo F, Helbling-Leclerc A, D’Apice MR, Massart C, Capon F, Sbraccia P, Federici M, Lauro R et al (2002) Mandibuloacral dysplasia is caused by a mutation in LMNA-encoding lamin A/C. Am J Hum Genet 71:426-431.
• Okada A, Kohmoto T, Naruto T, Yokota I, Kotani Y, Shimada A, Miyamoto Y, Takahashi R, Goji A, Masuda K et al (2017) The first Japanese patient with mandibular hypoplasia, deafness, progeroid features and lipodystrophy diagnosed via POLD1 mutation detection. Hum Genome Var 4:17031.
• Ou M-Y, Zhang H, Tan P-C, Zhou S-B and Li Q-F (2022) Adipose tissue aging: Mechanisms and therapeutic implications. Cell Death Dis 13:300.
• Pallotta R and Morgese G (1984) Mandibuloacral dysplasia: A rare progeroid syndrome. Two brothers confirm autosomal recessive inheritance. Clin Genet 26:133-138.
• Palmer AK, Xu M, Zhu Y, Pirtskhalava T, Weivoda MM, Hachfeld CM, Prata LG, van Dijk TH, Verkade E, Casaclang-Verzosa G et al (2019) Targeting senescent cells alleviates obesity-induced metabolic dysfunction. Aging Cell 18:e12950.
• Paolacci S, Bertola D, Franco J, Mohammed S, Tartaglia M, Wollnik B and Hennekam RC (2017) Wiedemann-Rautenstrauch syndrome: A phenotype analysis. Am J Med Genet A 173:1763-1772.
• Park SK, Chang SH, Cho SB, Baek HS and Lee DY (1994) Cockayne syndrome: A case with hyperinsulinemia and growth hormone deficiency. J Korean Med Sci 9:74-77.
• Parton RG (2018) Caveolae: Structure, function, and relationship to disease. Annu Rev Cell Dev Biol 34:111-136.
• Patel AG, Sarkaria JN and Kaufmann SH (2011) Nonhomologous end joining drives poly(ADP-ribose) polymerase (PARP) inhibitor lethality in homologous recombination-deficient cells. Proc Natl Acad Sci U S A 108:3406-3411.
• Patni N and Garg A (2015) Congenital generalized lipodystrophies-new insights into metabolic dysfunction. Nat Rev Endocrinol 11:522-534.
• Pelosini C, Martinelli S, Ceccarini G, Magno S, Barone I, Basolo A, Fierabracci P, Vitti P, Maffei M and Santini F (2014) Identification of a novel mutation in the polymerase delta 1 (POLD1) gene in a lipodystrophic patient affected by mandibular hypoplasia, deafness, progeroid features (MDPL) syndrome. Metabolism 63:1385-1389.
• Pendás AM, Zhou Z, Cadiñanos J, Freije JMP, Wang J, Hultenby K, Astudillo A, Wernerson A, Rodríguez F, Tryggvason K et al (2002) Defective prelamin A processing and muscular and adipocyte alterations in Zmpste24 metalloproteinase-deficient mice. Nat Genet 31:94-99.
• Peters JM, Barnes R, Bennett L, Gitomer WM, Bowcock AM and Garg A (1998) Localization of the gene for familial partial lipodystrophy (Dunnigan variety) to chromosome 1q21-22. Nat Genet18:292-295.
• Ponte CMM, Fernandes VO, Gurgel MHC, Vasconcelos ITGF, Karbage LBdAS, Liberato CBR, Negrato CA, Gomes MdB, Montenegro APDR and Montenegro Júnior RM (2018) Early commitment of cardiovascular autonomic modulation in Brazilian patients with congenital generalized lipodystrophy. BMC Cardiovasc Disord 18:6.
• Prokocimer M, Barkan R and Gruenbaum Y (2013) Hutchinson-Gilford progeria syndrome through the lens of transcription. Aging Cell 12:533-543.
• Puente XS, Quesada V, Osorio FG, Cabanillas R, Cadiñanos J, Fraile JM, Ordóñez GR, Puente DA, Gutiérrez-Fernández A, Fanjul-Fernández M et al (2011) Exome sequencing and functional analysis identifies BANF1 mutation as the cause of a hereditary progeroid syndrome. Am J Hum Genet 88:650-656.
• Qiang L, Wang H and Farmer SR (2007) Adiponectin secretion is regulated by SIRT1 and the endoplasmic reticulum oxidoreductase Ero1-L alpha. Mol Cell Biol 27:4698-4707.
• Rajab A, Straub V, McCann LJ, Seelow D, Varon R, Barresi R, Schulze A, Lucke B, Lützkendorf S, Karbasiyan M et al (2010) Fatal cardiac arrhythmia and long-QT syndrome in a new form of congenital generalized lipodystrophy with muscle rippling (CGL4) due to PTRF-CAVIN mutations. PLoS Genet 6:e1000874.
• Rautenstrauch T, Snigula F, Krieg T, Gay S and Müller PK (1977) Progeria: A cell culture study and clinical report of familial incidence. Eur J Pediatr 124:101-111.
• Reinier F, Zoledziewska M, Hanna D, Smith JD, Valentini M, Zara I, Berutti R, Sanna S, Oppo M, Cusano R et al (2015) Mandibular hypoplasia, deafness, progeroid features and lipodystrophy (MDPL) syndrome in the context of inherited lipodystrophies. Metabolism 64:1530-1540.
• Ren B, Cam H, Takahashi Y, Volkert T, Terragni J, Young RA and Dynlacht BD (2002) E2F integrates cell cycle progression with DNA repair, replication, and G(2)/M checkpoints. Genes Dev 16:245-256.
• Ren Y, Li Y, Yan J, Ma M, Zhou D, Xue Z, Zhang Z, Liu H, Yang H, Jia L et al (2017) Adiponectin modulates oxidative stress-induced mitophagy and protects C2C12 myoblasts against apoptosis. Sci Rep 7:3209.
• Richards SA, Muter J, Ritchie P, Lattanzi G and Hutchison CJ (2011) The accumulation of un-repairable DNA damage in laminopathy progeria fibroblasts is caused by ROS generation and is prevented by treatment with N-acetyl cysteine. Hum Mol Genet 20:3997-4004.
• Rodríguez AJ, Nunes VDS, Mastronardi CA, Neeman T and Paz-Filho GJ (2016) Association between circulating adipocytokine concentrations and microvascular complications in patients with type 2 diabetes mellitus: A systematic review and meta-analysis of controlled cross-sectional studies. J Diabetes Complications 30:357-367.
• Rohde K, Rønningen T, La Cour Poulsen L, Keller M, Blüher M and Böttcher Y (2020) Role of the DNA repair genes H2AX and HMGB1 in human fat distribution and lipid profiles. BMJ Open Diabetes Res Care 8:e000831.
• Rose M, Bai B, Tang M, Cheong CM, Beard S, Burgess JT, Adams MN, O’Byrne KJ, Richard DJ, Gandhi NS et al (2021) The impact of rare human variants on barrier-to-auto-integration factor 1 (Banf1) structure and function. Front Cell Dev Biol 9:775441.
• Rosen ED and Spiegelman BM (2000) Molecular regulation of adipogenesis. Annu Rev Cell Dev Biol 16:145-171.
• Rosen ED and Spiegelman BM (2006) Adipocytes as regulators of energy balance and glucose homeostasis. Nature 444:847-853.
• Rubio-Cabezas O, Puri V, Murano I, Saudek V, Semple RK, Dash S, Hyden CSS, Bottomley W, Vigouroux C, Magré J et al (2009) Partial lipodystrophy and insulin resistant diabetes in a patient with a homozygous nonsense mutation in CIDEC. EMBO Mol Med 1:280-287.
• Ruijs MWG, Van Andel RNJ, Oshima J, Madan K, Nieuwint AWM and Aalfs CM (2003) Atypical progeroid syndrome: An unknown helicase gene defect? Am J Med Genet A 116A:295-299.
• Salo VT, Belevich I, Li S, Karhinen L, Vihinen H, Vigouroux C, Magré J , Thiele C, Hölttä‐Vuori M, Jokitalo E et al (2016) Seipin regulates ER-lipid droplet contacts and cargo delivery. EMBO J 35:2699-2716.
• Salo VT, Li S, Vihinen H, Hölttä-Vuori M, Szkalisity A, Horvath P, Belevich I, Peränen J, Thiele C, Somerharju P et al (2019) Seipin facilitates triglyceride flow to lipid droplet and counteracts droplet ripening via endoplasmic reticulum contact. Dev Cell 50:478-493.e9.
• Sampath H, Batra AK, Vartanian V, Carmical JR, Prusak D, King IB, Lowell B, Earley LF, Wood TG, Marks DL et al (2011) Variable penetrance of metabolic phenotypes and development of high-fat diet-induced adiposity in NEIL1-deficient mice. Am J Physiol Endocrinol Metab 300:E724-734.
• Sampath H, Vartanian V, Rollins MR, Sakumi K, Nakabeppu Y and Lloyd RS (2012) 8-oxoguanine DNA glycosylase (OGG1) deficiency increases susceptibility to obesity and metabolic dysfunction. PLoS One 7:e51697.
• Sancar A, Lindsey-Boltz LA, Ünsal-Kaçmaz K and Linn S (2004) Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints. Annu Rev Biochem 73:39-85.
• Sasaki H, Yanagi K, Ugi S, Kobayashi K, Ohkubo K, Tajiri Y, Maegawa H, Kashiwagi A and Kaname T (2018) Definitive diagnosis of mandibular hypoplasia, deafness, progeroid features and lipodystrophy (MDPL) syndrome caused by a recurrent de novo mutation in the POLD1 gene. Endocr J65:227-238.
• Savage DB, Tan GD, Acerini CL, Jebb SA, Agostini M, Gurnell M, Williams RL, Umpleby AM, Thomas EL, Bell JD et al (2003) Human metabolic syndrome resulting from dominant-negative mutations in the nuclear receptor peroxisome proliferator-activated receptor-gamma. Diabetes52:910-917.
• Saxena S and Kumar S (2020) Pharmacotherapy to gene editing: Potential therapeutic approaches for Hutchinson-Gilford progeria syndrome. Geroscience 42:467-494.
• Scardoni G, Petterlini M and Laudanna C (2009) Analyzing biological network parameters with CentiScaPe. Bioinformatics 25:2857-2859.
• Scheibye-Knudsen M, Scheibye-Alsing K, Canugovi C, Croteau DL and Bohr VA (2013) A novel diagnostic tool reveals mitochondrial pathology in human diseases and aging. Aging (Albany NY) 5:192-208.
• Schosserer M, Grillari J, Wolfrum C and Scheideler M (2018) Age-induced changes in white, brite, and brown adipose depots: A mini-review. Gerontology 64:229-236.
• Schrauwen I, Szelinger S, Siniard AL, Kurdoglu A, Corneveaux JJ, Malenica I, Richholt R, Van Camp G, De Both M, Swaminathan S et al (2015) A frame-shift mutation in CAV1 is associated with a severe neonatal progeroid and lipodystrophy syndrome. PLoS One 10:e0131797.
• Schumacher B, Pothof J, Vijg J and Hoeijmakers JHJ (2021) The central role of DNA damage in the ageing process. Nature 592:695-703.
• Sepehri S and Hernandez N (1997) The largest subunit of human RNA polymerase III is closely related to the largest subunit of yeast and trypanosome RNA polymerase III. Genome Res 7:1006-1019.
• Shackleton S, Smallwood DT, Clayton P, Wilson LC, Agarwal AK, Garg A and Trembath RC (2005) Compound heterozygous ZMPSTE24 mutations reduce prelamin A processing and result in a severe progeroid phenotype. J Med Genet 42:e36.
• Shan T, Liu W and Kuang S (2013) Fatty acid binding protein 4 expression marks a population of adipocyte progenitors in white and brown adipose tissues. FASEB J 27:277-287.
• Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, Amin N, Schwikowski B and Ideker T (2003) Cytoscape: A software environment for integrated models of biomolecular interaction networks. Genome Res 13:2498-2504.
• Shastry S, Simha V, Godbole K, Sbraccia P, Melancon S, Yajnik CS, Novelli G, Kroiss M and Garg A (2010) A novel syndrome of mandibular hypoplasia, deafness, and progeroid features associated with lipodystrophy, undescended testes, and male hypogonadism. J Clin Endocrinol Metab 95:E192-7.
• Sim MFM, Persiani E, Talukder MMU, Mcilroy GD, Roumane A, Edwardson JM and Rochford JJ (2020) Oligomers of the lipodystrophy protein seipin may co-ordinate GPAT3 and AGPAT2 enzymes to facilitate adipocyte differentiation. Sci Rep 10:3259.
• Simha V and Garg A (2003) Phenotypic heterogeneity in body fat distribution in patients with congenital generalized lipodystrophy caused by mutations in the AGPAT2 or seipin genes. J Clin Endocrinol Metab 88:5433-5437.
• Smith U, Li Q, Rydén M and Spalding KL (2021) Cellular senescence and its role in white adipose tissue. Int J Obes (Lond) 45:934-943.
• Silberpfennig J, Schlesinger B, Faragó I, Bürki E, Wilder J, Wolf-Heidegger G, Helsmoortel J, Myle G, Kessler E, Ectors L et al (1941) Sur un syndrome progressif comprenant des télangiectasies capillaires cutanées et conjonctivales symétriques, à disposition naevoïde et des troubles cérébelleux. Stereotact Funct Neurosurg 4:32-42.
• Stevnsner T, Nyaga S, De Souza-Pinto NC, Van der Horst GTJ, Gorgels TGMF, Hogue BA, Thorslund T and Bohr VA (2002) Mitochondrial repair of 8-oxoguanine is deficient in Cockayne syndrome group B. Oncogene 21:8675-8682.
• Stevnsner T, Muftuoglu M, Aamann MD and Bohr VA (2008) The role of Cockayne syndrome group B (CSB) protein in base excision repair and aging. Mech Ageing Dev 129:441-448.
• Stingele J, Bellelli R, Alte F, Hewitt G, Sarek G, Maslen SL, Tsutakawa SE, Borg A, Kjær S, Tainer JA et al (2016) Mechanism and regulation of DNA-protein crosslink repair by the DNA-dependent metalloprotease SPRTN. Mol Cell 64:688-703.
• Szklarczyk D, Morris JH, Cook H, Kuhn M, Wyder S, Simonovic M, Santos A, Doncheva NT, Roth A, Bork P et al (2017) The STRING database in 2017: Quality-controlled protein-protein association networks, made broadly accessible. Nucleic Acids Res 45:D362-D368.
• Takagi M, Uno H, Nishi R, Sugimoto M, Hasegawa S, Piao J, Ihara N, Kanai S, Kakei S, Tamura Y et al (2015) ATM regulates adipocyte differentiation and contributes to glucose homeostasis. Cell Rep 10:957-967.
• Takemoto M, Mori S, Kuzuya M, Yoshimoto S, Shimamoto A, Igarashi M, Tanaka Y, Miki T and Yokote K (2013) Diagnostic criteria for Werner syndrome based on Japanese nationwide epidemiological survey. Geriatr Gerontol Int 13:475-481.
• Takenouchi T, Hida M, Sakamoto Y, Torii C, Kosaki R, Takahashi T and Kosaki K (2013) Severe congenital lipodystrophy and a progeroid appearance: Mutation in the penultimate exon of FBN1 causing a recognizable phenotype. Am J Med Genet A 161:3057-3062.
• Tan Y, Raychaudhuri P and Costa RH (2007) Chk2 Mediates Stabilization of the FoxM1 Transcription Factor To Stimulate Expression of DNA Repair Genes. Mol Cell Biol 27:1007-1016.
• Tanaka K (1993) Molecular analysis of xeroderma pigmentosum group A gene. Jap J Hum Genet 38:1-14.
• Tchkonia T, Morbeck DE, Von Zglinicki T, Van Deursen J, Lustgarten J, Scrable H, Khosla S, Jensen MD and Kirkland JL (2010) Fat tissue, aging, and cellular senescence. Aging Cell 9:667-684.
• Tenconi R, Miotti F, Miotti A, Audino G, Ferro R and Clementi M (1986) Another Italian family with mandibuloacral dysplasia: Why does it seem more frequent in Italy?. Am J Med Genet 24:357-364.
• Tiku V and Antebi A (2018) Nucleolar function in lifespan regulation. Trends Cell Biol 28:662-672.
• Tuo J, Chen C, Zeng X, Christiansen M and Bohr VA (2002) Functional crosstalk between hOgg1 and the helicase domain of Cockayne syndrome group B protein. DNA Repair (Amst) 1:913-927.
• Turaga RVN, Paquet ER, Sild M, Vignard J, Garand C, Johnson FB, Masson JY and Lebel M (2009) The Werner syndrome protein affects the expression of genes involved in adipogenesis and inflammation in addition to cell cycle and DNA damage responses. Cell Cycle 8:2080-2092.
• Unger RH (2005) Longevity, lipotoxicity and leptin: the adipocyte defense against feasting and famine. Biochimie 87:57-64.
• Van Der Pluijm I, Garinis GA, Brandt RMC, Gorgels TGMF, Wijnhoven SW, Diderich KEM, De Wit J, Mitchell JR, Van Oostrom C, Beems R et al (2007) Impaired genome maintenance suppresses the growth hormone-insulin-like growth factor 1 axis in mice with cockayne syndrome. PLoS Biol 5:e2.
• Varela I, Cadiñanos J, Pendás AM, Gutiérrez-Fernández A, Folgueras AR, Sánchez LM, Zhou Z, Rodríguez FJ, Stewart CL, Vega JA et al (2005) Accelerated ageing in mice deficient in Zmpste24 protease is linked to p53 signalling activation. Nature 437:564-568.
• Vartanian V, Lowell B, Minko IG, Wood TG, Ceci JD, George S, Ballinger SW, Corless CL, McCullough AK and Lloyd RS (2006) The metabolic syndrome resulting from a knockout of the NEIL1 DNA glycosylase. Proc Natl Acad Sci U S A 103:1864-1869.
• Vartanian V, Tumova J, Dobrzyn P, Dobrzyn A, Nakabeppu Y, Lloyd RS and Sampath H (2017) 8-oxoguanine DNA glycosylase (OGG1) deficiency elicits coordinated changes in lipid and mitochondrial metabolism in muscle. PLoS One 12:e0181687.
• Vaz B, Popovic M, Newman JA, Fielden J, Aitkenhead H, Halder S, Singh AN, Vendrell I, Fischer R, Torrecilla I et al (2016) Metalloprotease SPRTN/DVC1 orchestrates replication-coupled DNA-protein crosslink repair. Mol Cell64:704-719.
• Vessoni AT, Guerra CCC, Kajitani GS, Nascimento LLS and Garcia CCM (2020) Cockayne syndrome: The many challenges and approaches to understand a multifaceted disease. Genet Mol Biol43:e20190085.
• Vigouroux C, Caron-Debarle M, Le Dour C, Magré J and Capeau J (2011) Molecular mechanisms of human lipodystrophies: From adipocyte lipid droplet to oxidative stress and lipotoxicity. Int J Biochem Cell Biol 43:862-876.
• Von Bank H, Kirsh C and Simcox J (2021) Aging adipose: Depot location dictates age-associated expansion and dysfunction. Ageing Res Rev 67:101259.
• Wajchenberg BL (2000) Subcutaneous and visceral adipose tissue: Their relation to the metabolic syndrome. Endocr Rev 21:697-738.
• Wambach JA, Wegner DJ, Patni N, Kircher M, Willing MC, Baldridge D, Xing C, Agarwal AK, Vergano SAS, Patel C et al (2018) Bi-allelic POLR3A loss-of-function variants cause autosomal-recessive Wiedemann-Rautenstrauch syndrome. Am J Hum Genet 103:968-975.
• Wang H, Becuwe M, Housden BE, Chitraju C, Porras AJ, Graham MM, Liu XN, Thiam AR, Savage DB, Agarwal AK et al (2016) Seipin is required for converting nascent to mature lipid droplets. eLife5:e16582.
• Wang LR, Radonjic A, Dilliott AA, McIntyre AD and Hegele RA (2018) A de novo POLD1 mutation associated with mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome in a family with Werner syndrome. J Investig Med High Impact Case Rep 6:2324709618786770.
• Weedon MN, Ellard S, Prindle MJ, Caswell R, Allen HL, Oram R, Godbole K, Yajnik CS, Sbraccia P, Novelli G et al (2013) An in-frame deletion at the polymerase active site of POLD1 causes a multisystem disorder with lipodystrophy. Nat Genet 45:947-950.
• Weissman L, de Souza-Pinto NC, Stevnsner T and Bohr VA (2007) DNA repair, mitochondria, and neurodegeneration. Neuroscience 145:1318-1329.
• Werner M, Thuriaux P and Soutourina J (2009) Structure-function analysis of RNA polymerases I and III. Curr Opin Struct Biol 19:740-745.
• Werner O (1985) On cataract in conjunction with scleroderma. Adv Exp Med Biol 190:1-14.
• Wiedemann HR (1979) An unidentified neonatal progeroid syndrome: Follow-up report. Eur J Pediatr 130:65-70.
• Wu SW, Li L, Feng F, Wang L, Kong YY, Liu XW and Yin C (2021) Whole-exome sequencing reveals POLR3B variants associated with progeria-related Wiedemann-Rautenstrauch syndrome. Ital J Pediatr 47:160.
• Yaou RB, Navarro C, Quijano-Roy S, Bertrand AT, Massart C, De Sandre-Giovannoli A, Cadĩanos J, Mamchaoui K, Butler-Browne G, Estournet B et al (2011) Type B mandibuloacral dysplasia with congenital myopathy due to homozygous ZMPSTE24 missense mutation. Eur J Hum Genet 19:647-654.
• Young LW, Radebaugh JF, Rubin P, Sensenbrenner JA, Fiorelli G and McKusick MV (1971) New syndrome manifested by mandibular hypoplasia, acroosteolysis, stiff joints and cutaneous atrophy (mandibuloacral dysplasia) in two unrelated boys. Birth Defects Orig Artic Ser 7:291-297.
• Yu CE, Oshima J, Fu YH, Wijsman EM, Hisama F, Alisch R, Matthews S, Nakura J, Miki T, Ouais S et al (1996) Positional cloning of the Werner’s syndrome gene. Science 272:258-262.
• Yu K, Mo D, Wu M, Chen H, Chen L, Li M and Chen Y (2014) Activating transcription factor 4 regulates adipocyte differentiation via altering the coordinate expression of CCATT/enhancer binding protein β and peroxisome proliferator-activated receptor γ. FEBS J 281:2399-2409.
• Yu PT, Luk HM, Mok MT and Lo FI (2021) Evolving clinical manifestations of mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome: From infancy to adulthood in a 31-year-old woman. Am J Med Genet A 185:995-998.
• Zammouri J, Vatier C, Capel E, Auclair M, Storey-London C, Bismuth E, Mosbah H, Donadille B, Janmaat S, Fève B et al (2021) Molecular and cellular bases of lipodystrophy syndromes. Front Endocrinol (Lausanne) 12:803189.
• Zhang H, Xiong ZM and Cao K (2014) Mechanisms controlling the smooth muscle cell death in progeria via down-regulation of poly(ADP-ribose) polymerase 1. Proc Natl Acad Sci U S A 111:E2261-E2270.
• Zhang N, Wu X, Yang L, Xiao F, Zhang H, Zhou A, Huang Z and Huang S (2012) FoxM1 inhibition sensitizes resistant glioblastoma cells to temozolomide by downregulating the expression of DNA repair gene Rad51. Clin Cancer Res 18:5961-5971.
• Zina AM, Cravario A and Bundino S (1981) Familial mandibuloacral dysplasia. Br J Dermatol 105:719-723.
• Zolotov S, Xing C, Mahamid R, Shalata A, Sheikh-Ahmad M and Garg A (2017) Homozygous LIPE mutation in siblings with multiple symmetric lipomatosis, partial lipodystrophy, and myopathy. Am J Med Genet A 173:190-194.
• Zona S, Bella L, Burton MJ, Nestal de Moraes G and Lam EWF (2014) FOXM1: An emerging master regulator of DNA damage response and genotoxic agent resistance. Biochim Biophys Acta1839:1316-1322.

Internet Resources

• Servier Medical ART. Les Laboratoires Servier SMART. https://smart.servier.com (accessed 11 November 2021).
  » https://smart.servier.com

Edited by

Associate Editor:

Carlos F. M. Menck

Publication Dates

• Publication in this collection
  07 Nov 2022
• Date of issue
  2022

History

• Received
  11 Mar 2022
• Accepted
  20 Sept 2022