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. Author manuscript; available in PMC: 2022 Apr 1.
Published in final edited form as: J Invest Dermatol. 2021 Jan 19;141(4 Suppl):968–975. doi: 10.1016/j.jid.2020.10.019

Skin abnormalities in disorders with DNA repair defects, premature aging, and mitochondrial dysfunction

Mansoor Hussain 1, Sudarshan Krishnamurthy 1, Jaimin Patel 1, Edward Kim 1, Beverly A Baptiste 1, Deborah L Croteau 1, Vilhelm A Bohr 1
PMCID: PMC7987691  NIHMSID: NIHMS1645303  PMID: 33353663

Abstract

Defects in DNA repair pathways and alterations of mitochondrial energy metabolism have been reported in multiple skin disorders. More than ten percent of patients with primary mitochondrial dysfunction exhibit dermatological features including rashes and hair and pigmentation abnormalities. Accumulation of oxidative DNA damage and dysfunctional mitochondria affect cellular homeostasis leading to increased apoptosis. Emerging evidence demonstrates that genetic disorders of premature aging that alter DNA repair pathways and cause mitochondrial dysfunction, such as Rothmund-Thomson syndrome, Werner’s syndrome, and Cockayne syndrome, also exhibit skin disease. This article summarizes recent advances in the research of those syndromes and molecular mechanisms underlying their skin pathologies.

Keywords: DNA repair, Skin disorders, Mitochondrial dysfunction, premature aging

INTRODUCTION

Cellular and environmental stimuli play major roles in skin diseases. DNA repair is necessary to maintain cellular function and involves several pathways and proteins. Mutation of a single DNA repair protein, accompanied by environmental stress, can manifest in a variety of diseases. DNA repair pathways are important for skin health.

DNA repair pathways include nucleotide excision repair (NER), base excision repair (BER), mismatch repair (MMR) and DNA double strand break repair (DSBR). NER has been well studied in in skin disorders, as defects in many NER proteins results in the premature aging disorder, xeroderma pigmentosum (XP). XP patients manifest extreme skin aging and disease. This topic has been reviewed extensively (Aboussekhra et al., 1995, Scharer, 2013, Wakasugi et al., 2014).

Our lab and others have demonstrated that NAD+ supplementation improves mitochondrial health in several DNA repair-deficient disorders (Fang et al., 2019, Fang et al., 2016a). Diseases that result in accumulation of DNA damage are accompanied by constitutively active poly(ADP-ribosyl)ation, catalyzed by (ADP)-ribosyl transferase (ADPRT). Poly (ADP-ribosyl)ation is a process that consumes NAD+, thereby limiting the activity of other NAD+- dependent enzymes, including sirtuins, deacetylases with important roles in DNA repair. Thus, limited NAD+ results in decreased DNA repair. ADPRT knockout mice were susceptible to spontaneous skin lesions and increased epidermal hyperplasia, suggesting that poly(ADP-ribosyl)ation might be important in the development of skin disorders (Wang et al., 1995). NAD+ improves defects in neurodegeneration (Fang et al., 2016a, Ralto et al., 2020) and the ratio of NAD+/NADH is important for dynamic regulation of mitochondrial metabolism and function. Replenishment of NAD+ improves mitochondrial homeostasis and mitochondrial morphology by promoting mitophagy in repair-deficient cells (Fang et al., 2019, Fang et al., 2016b, Ralto et al., 2020, Scheibye-Knudsen et al., 2014). In this review, we focus on DNA repair and three non-XP DNA repair-deficient genetic disorders with skin manifestations: Cockayne syndrome (CS), Rothmund-Thomson syndrome (RTS), and Werner’s syndrome (WS) and on the skin diseases associated with these genetic disorders of premature aging and DNA repair, summarized in Table 1. In particular, we emphasize recent advances in understanding how DNA repair pathways are altered in these disorders, and how this results in skin pathologies.

Table 1.

DNA Repair disorders with the respective genetic mutations indicated, DNA repair defects, mitochondrial defects, and accompanying dermatological manifestations observed

Disorder Genetic Mutations DNA Repair Defects Mitochondrial Defects Dermatological Manifestations
Rothmund-Thomson Syndrome RECQL4 BER; unscheduled DNA synthesis; NHEJ; HR Mitochondrial Dysfunction and accumulation of mtDNA mutations Poikiloderma, Hypo/Hyperpigmentation, Atopic Dermatitis
Cockayne Syndrome CSA, CSB TC-NER Mitochondrial dysfunction; Increased mitochondrial metabolism, ATP and oxygen consumption; defective mitophagy Photosensitivity, Pigmentation, Scarring, Inflammation, Anhidrosis, Thin/Dry Hair, Thinning of Epidermis
Werner Syndrome WRN TC-NER; BER; Recombination Mitochondrial dysfunction; Diminished mitophagy; Increased mitochondrial ROS Hyperkeratosis, Abnormal pigmentation, Hair loss and graying, Skin wrinkling
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BER: Base excision repair, TC-NER: transcription coupled - nucleotide excision repair, ROS: reactive oxygen species, mtDNA: mitochondrial DNA, NHEJ: non-homologous end-joining HR: homologous recombination

Cockayne Syndrome

CS is an extremely rare autosomal recessive disorder comprised of two main complementation groups, CSA and CSB. CSA and CSB patients contain mutations in the ERCC8 or ERCC6 genes, respectively (Natale, 2011). Although estimates vary, mutations in CSB accounts for 62–78% of the mutations in CS patients (Laugel et al., 2010, Stefanini et al., 1996). The phenotypic spectra of patients with mutations in CSA or CSB overlap and differ mostly in severity (Laugel et al., 2010).

Molecular Pathophysiology of Cockayne Syndrome

At the molecular level, CS is characterized by defects in transcription and transcription-coupled nucleotide excision repair (TC-NER) (Karikkineth et al., 2017, Mayne and Lehmann, 1982), resulting in sensitivity to ultraviolet radiation (UVR) and failure to recover RNA synthesis after exposure to UVR (Andrews et al., 1978, Mayne and Lehmann, 1982). It has been hypothesized that the decreased rate and extent of DNA repair of transcribed genes in CS models is closely linked to the sensitivity to UV radiation (van Hoffen et al., 1993).

CSA and CSB have also been implicated in regulation of ribosomal biogenesis through interactions with a nucleolar protein that regulates rRNA synthesis, nucleolin (Ncl) (Okur et al., 2020). Ribosomal biogenesis is highly energy consuming and tightly regulated. One pathway regulating energy consumption is the mTOR pathway (Okur et al., 2020, Saxton and Sabatini, 2017). The loss of rDNA transcription in CSA- and CSB-deficient cells results in constitutive activation of mTOR, leading to mitochondrial dysfunction and defective metabolic homeostasis (Okur et al., 2020, Saxton and Sabatini, 2017, Scheibye-Knudsen et al., 2016).

CS models exhibit metabolic and mitochondrial defects (Pascucci et al., 2012, Scheibye-Knudsen et al., 2014). We have found that CSB-deficient mice exhibit increased mitochondrial metabolism in the form of increased oxygen consumption, hyperpolarized mitochondria and increased mitochondrial volume (Scheibye-Knudsen et al., 2012). Mitochondrial and metabolic defects in CS were rescued through activation of SIRT1 and increased levels of NAD+ using a high-fat diet (HFD), PARP1 inhibition, or β-hydroxybutyrate supplementation (Scheibye-Knudsen et al., 2014). CSB localizes to mitochondria in stress conditions and plays a protective role in mitochondrial autophagy (mitophagy) and mitochondrial BER (Aamann et al., 2010, Scheibye-Knudsen et al., 2012).

Nuclear-mitochondrial crosstalk has also been proposed as an explanation for mitochondrial dysfunction as a response to nuclear DNA damage in CS models (Scheibye-Knudsen et al., 2013). ATM activation and consumption of NAD+ because of increased poly(ADP-ribosyl)ation and lower ATP levels could account for increased metabolism, while increased levels of reactive oxygen species (ROS) and membrane potential changes are likely responsible for increased dysfunctional mitochondria (Scheibye-Knudsen et al., 2013). Defective mitophagy pathways contribute to accumulation of damaged mitochondria seen in CS models (Lee et al., 2019).

Dermatological Manifestations of Cockayne Syndrome

CS patients present with several dermatological complications including photosensitivity, pigmentation, scarring, thinning of epidermis with absence of rete ridges, and scattered patches of chronic inflammation in the upper dermis. Anhidrosis, thin and dry hair, nail dystrophy, skin atrophy, cyanotic livedo, and edema in extremities are other dermatological features reported in CS patients (Laugel, 2013). Evidence indicates that individuals with CS typically have underdeveloped eccrine sweat glands that are smaller than those of individuals without chromosomal or genetic disorders (Landing et al., 1983), consistent with the clinical feature of anhidrosis. Cutaneous photosensitivity has been established as a key feature of CS, and is clinically prevalent in 67–75% of these individuals (Laugel, 2013). Increased susceptibility to UV-induced chromosomal aberrations, and other previously stated molecular defects, indicate that cytotoxic effects of UVR are likely associated with the clinical presentation of cutaneous photosensitivity (Otsuka and Robbins, 1985, Seguin et al., 1988).

Chronic inflammation and thinning of the epidermis could be attributed to mitochondrial dysfunction as inflammasome activation and cell death are features known to accompany damaged mitochondria (Missiroli et al., 2020). Keratinocytes isolated from individuals lacking CSA exhibit features of premature senescence. Senescent cells produce a senescence-associated secretory phenotype (SASP) resulting in accumulation of high levels of inflammatory cytokines and chemokines in the surrounding microenvironment (Coppe et al., 2010, Cordisco et al., 2019), leading to loss of tissue homeostasis. Mitochondrial defects are also known to be associated with an inflammatory phenotype, leading to further mitochondrial dysfunction, promoting a vicious cycle (Lopez-Armada et al., 2013). Supplementation with nicotinamide riboside (NR), a precursor of NAD+, has been shown to rescue mitochondrial defects in CS, decreasing mitochondrial ROS production and mitochondrial membrane potential (Scheibye-Knudsen et al., 2014).

Unlike other DNA repair-deficient disorders, such as XP, skin cancers have not been reported in CS (Zhang et al., 2016). XP cells exhibit increased mutation frequencies compared to control cells, but the same is not seen with CS patients (Reid-Bayliss et al., 2016). Although the TC-NER deficiency increases cytotoxicity in CS, it is not mutagenic, while global genomic nucleotide excision repair (GG-NER) deficiencies (in addition to deficient TC-NER) in XP result in UV-induced mutagenesis and increased incidence of cancer (Reid-Bayliss et al., 2016).

Rothmund-Thomson syndrome

RECQ helicases are the guardians of the genome. They are evolutionarily conserved from prokaryotes to eukaryotes and play a pivotal role in maintaining genomic integrity. In humans, there are five RECQ helicases, and mutations in three of these genes (WRN, BLM, RECQL4) are associated with Werner (WS), Bloom (BS) and Rothmund-Thomson (RTS) syndromes, respectively (Wu et al., 2000). RTS is a rare autosomal recessive disorder characterized by poikiloderma, skeletal abnormalities, and juvenile cataracts (Siitonen et al., 2009). RTS is associated with germline mutations in the RECQL4 gene, (Siitonen et al., 2009).

RECQL4 in DNA repair

Double strand breaks (DSB) are harmful forms of DNA damage leading to genomic instability, malignancy and cell death (Jackson and Bartek, 2009). DSB’s are repaired through two distinct pathways: homologous recombination (HR) and non-homologous end joining (NHEJ). Fibroblasts isolated from RTS patients and RECQL4 knockout cell lines exhibited sensitivity to ionizing radiation (IR) and rapid accumulation of RECQL4 at DSBs, suggesting that RECQL4 plays important role in DNA repair (Singh et al., 2010). Recently, we have shown that RECQL4 functions in both HR and NHEJ pathways (Shamanna et al., 2014). Our findings demonstrated that RECQL4 physically associated with MRN (MRE11-RAD50, NBS1) complex, which senses DSBs, and promotes DNA end resection via CtIP (Lu et al., 2016). Further, RECQL4’s interaction with CtIP has been shown to enhance CtIP’s recruitment at the site of DSBs, thereby promoting HR-dependent repair (Lu et al., 2016). Interestingly, RECQL4 knockout cells showed significant reduction in NHEJ repair likely due to that RECQL4 interacts with the Ku70/Ku80 complex., (Shamanna et al., 2014).

RECQL4 also plays a role in BER. Microarray analysis revealed downregulation of the BER pathway genes upon oxidative stress in RTS patient cells as compared to control cells (Schurman et al., 2009). Upon oxidative stress, RECQL4 associates with and enhances the activity of BER proteins including OGG1, APE1, Polβ and FEN1 (Flap-endonuclease 1) (Duan et al., 2020). RECQL4 associated with OGG1 and stimulated its glycosylase and AP lyase activity in vitro. Oxidative stress induces hyperacetylation of RECQL4 and enhanced its interaction with OGG1. After DNA repair, RECQL4 is deacetylated by SIRT1, a de-acetylase, and this association hampers the interaction between RECQL4 and OGG1 (Duan et al., 2020). Interestingly, RECQL4-deficient cells show accumulation of 8-oxoG in genomic DNA and hence increased genomic instability (Duan et al., 2020).

Mitochondrial dysfunctions in RTS-deficient cells

RECQL4 has roles in both the nucleus and in mitochondria. In the mitochondria, RECQL4 functions in mtDNA replication (Croteau et al., 2012a, Croteau et al., 2012b, De et al., 2012) and interacts with the mitochondrial replicative proteins, PolγA and PolγB (Gupta et al., 2014). This interaction with PolγA facilitated better binding of PolγA to mtDNA and also increased its catalytic activity in vitro (Gupta et al., 2014). RTS patients exhibited accumulation of random mtDNA mutations, particularly in the D-loop region (Gupta et al., 2014). Cells lacking mitochondrial RECQL4 exhibited significant increase in mitochondrial ROS due to the presence of inactive mitochondrial SOD2 (Kumari et al., 2016). It is important to note that mtDNA mutations and altered metabolism are reported in multiple skin and hair abnormalities (Feichtinger et al., 2014). In summary, loss of RECQL4 function results in mitochondrial dysfunctions and accumulation of mtDNA mutations in cells.

Dermatological manifestations in RTS

Patients lacking RECQL4 function exhibit skin disorders including poikiloderma and skin rashes. Poikiloderma consists of three features: hyper- and hypopigmentation, telangiectasias, and atrophy. Approximately one third of RTS patients exhibit hyperkerastatic lesions, primarily on the soles of the feet (Wang and Plon, 1993). Loss of RECQL4-dependent DNA repair decreases cellular resilience (Jin et al., 2008, Schurman et al., 2009, Singh et al., 2010), which may contribute to cell death and atrophy. Additionally, loss of RECQL4 has been shown to increase senescence in cells (Lu et al., 2014) and senescence has been reported to contribute to hyper- and hypopigmentation (Bellei and Picardo, 2020).

Full knockout of RECQL4 protein in mice resulted in lethality at embryonic day 3–6 (Ichikawa et al., 2002). Knockout of the helicase domain resulted in viable mice that exhibited growth abnormalities and skin disorders. Notably, dry skin was observed in 60% of mutant mice at the age of 3–4 months and histological studies on skin samples revealed that mutant mice exhibited hypoplastic epidermis, dermis, and subcutaneous tissues, poikiloderma with hypo- and hyperpigmented skin on their tails (Hoki et al., 2003). RECQL4’s role in modulating vascular changes to promote telangiectasias awaits further analysis. Taken together, these studies indicate that RECQL4 plays an important role in skin health, however, the underlying molecular mechanisms needs further investigation.

Werner Syndrome

Patients suffering from WS typically experience normal development until they reach the second decade of their life, when symptoms of premature aging begin. They often experience age-related skin wrinkling, hair loss, and hair graying in their 20s and 30s, similar to what is typical in aged people (Mazzarello et al., 2018). They also have an increased risk of developing osteoporosis, neoplasms, diabetes mellitus, and atherosclerosis (Muftuoglu et al., 2008). In addition to skin damage associated with aging, a recent case report demonstrated that WS can also result in hyperkeratosis and abnormal skin pigmentation (Rincon et al., 2019). One of the most serious skin ailments in WS patients is severe skin ulcers, as they often lead to the need for amputation (Muftuoglu et al., 2008, Yeong and Yang, 2004). Therefore, uncovering the mechanisms underlying this debilitating pathological feature is an area of active research. The WRN gene encodes the WRN RecQ helicase. The WRN protein has a conserved helicase domain, RQC domain, HRDC domain, and a unique 3’−5’ exonuclease domain (Croteau et al., 2014). WRN is typically localized within the nucleolus but is shuttled into the nucleus upon DNA damage in a PARP1-dependent manner (Veith et al., 2019). WRN is maintained in the nucleolus in an inactive form and upon DNA damage WRN is released from this inhibition and participates in G4 DNA unwinding (Indig et al., 2012). WRN has been shown to interact with several DNA repair proteins involved in BER, NER and DSBR. For instance, WRN protein stimulates NEIL1, a glycosylase in the BER pathway, and DNA polymerase ß, the polymerase responsible for DNA resynthesis following the removal of damaged bases (Das et al., 2007, Harrigan et al., 2003). It has also been demonstrated that WRN plays a significant role in resolving oxidative DNA damage in slowly proliferating cells (Szekely et al., 2005). In the context of NER, WRN has been shown to interact with XPG (Trego et al., 2011) although the significance of that interaction is unknown. WRN also interacts with proteins in the c-NHEJ, alt-NHEJ, and HR pathways (Croteau et al., 2014). Specifically, it has been demonstrated that the WRN protein regulates the cell’s decision to undergo c-NHEJ or alt-NHEJ (Shamanna et al., 2016). WRN has also been shown to be critical in resolving stalled replication forks during replication stress (Mukherjee et al., 2018).

New research has implicated WRN in mitochondrial function. Many phenotypes in WS patients may be associated with mitochondrial dysfunction. These include diabetes, cancer, and atherosclerosis as well as skin aging and disease (Feichtinger et al., 2014, Madamanchi and Runge, 2007, Muftuoglu et al., 2008, Stout and Birch-Machin, 2019, Szendroedi et al., 2011, Wallace, 2012). WS model organisms exhibit mitochondrial dysfunction and diminished mitophagy, abnormal cristae structure, and mitochondrial density (Fang et al., 2019). It is important to note that WRN is not present in mitochondria, however it may associate on the outer mitochondrial membrane, suggesting that mitochondrial dysfunction in WRN deficient cells could be a secondary effect (Fang et al., 2019). Increasing evidence has suggested the significance of nuclear to mitochondrial signaling, specifically the relationship between DNA damage signaling and the mitochondria, in aging (Fang et al., 2016b). Thus, an area of further interest is how WRN activity modulates mitochondrial dynamics and function, as well as the role of nuclear to mitochondrial signaling in dermatological pathologies and skin aging.

WRN deficiency can also lead to increased mitochondrial ROS formation and induction of hypoxia inducible factor 1 α (HIF-1α) activity (Labbe et al., 2012). Oxidative stress has the potential to lead cells into senescence, and premature and extensive senescence in tissues is a hallmark of WS (Brandl et al., 2011, Davis et al., 2007, Han et al., 2016). Senescence has also been previously implicated in the pathology of chronic ulcers (Wall et al., 2008, Wang et al., 2019). Increased susceptibility to oxidative damage has also been specifically shown to be a characteristic of fibroblasts from chronic wound tissue (Wall et al., 2008). Therefore, premature senescence seen in WS may contribute to the chronic ulceration seen in this disease. It has been shown that senescence may also be beneficial for tissue repair (Demaria et al., 2014, Jun and Lau, 2010). However, excessive senescence may outweigh the beneficial role.

CONCLUSIONS

A wide range of skin disorders are associated with DNA repair deficiencies and premature aging syndromes. The disorders discussed above are rare autosomal recessive genetic disorders, with mild to severe skin abnormalities. Many studies from different laboratories have contributed to our limited understanding about skin disorders in these syndromes, but much remains to be discovered. While there are extensive skin studies done in CS, characterization of skin manifestations in RTS and WS are still not well studied. Unraveling how these proteins contribute to skin ailments, the role of the environmental stressors, and the underlying molecular mechanism have substantial potential to improve the quality of life of afflicted patients. Association of DNA repair deficiencies and mitochondrial dysfunctions have been reported repeatedly in RTS, WS, and CS. Interestingly, mtDNA does not encode DNA repair genes, therefore all repair proteins involved in mtDNA repair are imported. This leaves both the nuclear and mitochondrial genome entirely dependent on the nuclear-encoded proteins, which can contribute to mitochondrial dysfunction. For future treatment strategies it is important to consider interventions that can improve both DNA repair efficiency and mitochondrial function.

Many labs have focused on the restorative potential of NAD+ supplementation. Decreased NAD+ has been shown to be associated with aging and multiple diseases including neurodegenerative disorders, hearing loss, and cancer (Brown et al., 2014, Gujar et al., 2016, van der Veer et al., 2007), and NAD+ supplementation positively regulates DNA repair and mitochondrial health (Fang et al., 2019, Fang et al., 2016b). Further, it would be intriguing to study the effect of NAD+ on skin diseases with defects in DNA repair and mitochondrial dysfunctions. This could be a potential intervention to improve mitochondrial functions and regulate nuclear-mitochondrial signaling in patients with premature aging and skin abnormalities.

The DNA repair-deficient diseases reviewed here are rare genetic disorders, but their similarity to an accelerated version of the natural aging process drives continued research on these conditions and their associated genes. A good example of this is WS, which mimics most aging phenotypes closely, at an accelerated pace. WS patients appear much older, both in general appearance and medical phenotypes. These patients illustrate the role of WRN in slowing the natural aging process. An understanding that WS represented a true premature aging disorder led to animal, cellular, and biochemical studies into the protein, which revealed that WRN has multiple roles in DNA repair, thus highlighting DNA repair in the aging process (Bohr, 2005, Bohr et al., 2002, Shamanna et al., 2017). Likewise, CS and RTS lead to premature aging phenotypes, demonstrating a role for these proteins in natural aging. CS and RTS are also associated with DNA repair defects, further highlighting the importance of genome maintenance on healthy aging.

Consistent with these findings, in non-progeroid aged rodents and humans, DNA repair declines with age. These correlations have been repeated in assays of expression of repair proteins (Ju et al., 2006, Lu et al., 2004), as well as biochemical repair assays (Cabelof et al., 2002, Pons et al.,2010, Vaidya et al., 2014). Compellingly, studies of elite aging demonstrate increased expression of DNA repair factors in long lived species (Tian et al., 2019) and individuals within a species (Caruso et al., 2019), suggesting that increased DNA repair contributes to longer lifespans. The research presented in this review discusses the link between DNA repair, aging, mitochondrial dysfunction, and skin disorders. Work from our lab and others demonstrates that increasing DNA repair improves mitochondrial function and decreases age-related disease. Recent investigations into nuclear to mitochondrial signaling provides information on where interventions may be most effective in response to rate-limiting enzymes or substrates. Continued research into the DNA repair-mitochondrial function axis is needed to improve mitochondrial health due to disease or the aging process.

Figure 1: Dermatological manifestations in DNA repair deficit disorders.

Figure 1:

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Loss of function of DNA repair proteins like RECQL4, WRN and CS causes premature aging and altered nuclear-mitochondrial signaling. Accumulation of DNA damage and altered signaling attributes to mitochondrial dysfunctions such as increased ROS levels, mtDNA mutations, decreased NAD/NADH ratio and defective mitophagy. This likely contributes to the underlying cause of skin disorders in patients like Rothmund-Thompson, Werner and Cockayne syndrome. The model was created using Biorender.com.

Table 2.

Skin disorders associated with the respective gene mutations, mitochondrial defects, and dermatological manifestations.

Disease Mutation Mitochondrial dysfunction Skin Pathologies
Non-epidermolytic palmoplantar keratoderma (NEPPK) mtDNA - A7445G ETC complex IV subunit 1, and decreases cellular respiration Diffuse, homogeneous, mild to thick, yellowish palmoplantar hyperkeratosis (Maasz et al., 2008)
Dupuytren’s disease mtDNA - 16S rRNA Unknown Abnormal thickening of the skin of the hands (Burge, 1999)
Aplasia cutis congenita (APLCC) C0X7B Dissipated complex IV assembly and mitochondrial respiration Congenital absence of the epidermis (Indrieri et al., 2012)
Bjornstad syndrome BC1 (ubiquinol-cytochrome c reductase) synthesis-like protein defective complex III Twisted hair shaft and brittle hair (Lynn et al., 2012)
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Abbreviations:

BER

Base Excision Repair

NER

Nucleotide Excision Repair

WS

Werner syndrome

RTS

Rothmund-Thomson syndrome

CS

Cockayne syndrome

HR

Homologous Repair

NHEJ

Non-Homologous End Joining

UVR

Ultraviolet Radiation

Footnotes

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Conflicts of interest

The Bohr laboratory has a CRADA agreement with ChromaDex, a supplier of the NAD+ supplement nicotinamide riboside.

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