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Progeroid Syndromes and UV-Induced Oxidative DNA Damage York Kamenisch1 and Mark Berneburg1

Progeroid syndromes are a group of diseases char- Most progeroid syndromes include defects in acterized by signs of premature aging. These syn- different DNA repair systems, such as nucleotide excision dromes comprise diseases such as , repair (NER), (BER), and double strand , Rothmund–Thomson syndrome, break repair (DSBR). An increasing number of publications Hutchinson–Gilford syndrome, , and indicate that the accumulation of DNA damage is an ataxia–, as well as xeroderma pigmento- important mediator of aging (Schumacher et al., 2008) sum, , and . (Figure 1). Clinical symptoms of premature aging are In this review, the clinical features of progeroid syndromes with loss of cutaneous elasticity, dysfunction will be discussed briefly, and subsequently the genotoxic of cutaneous appendices, degeneration of the central effects of UV radiation will be communicated. Furthermore, as far as it is known, the underlying defects in DNA repair nervous system and an increased susceptibility for systems are introduced with a focus on their susceptibility to malignant tumors. Genetic defects in the repair of UV radiation-induced direct and indirect DNA damage in DNA damage can lead to progeroid syndromes, and it relation to progeroid syndromes. is becoming increasingly evident that direct DNA damage and indirect damage by highly reactive UV IRRADIATION AND oxygen species play central roles in aging. The clinical UV radiation is an important DNA stressor for skin cells. UVB signs of progeroid syndromes and the molecular and UVC especially cause several types of DNA damage, of aspects of UV ( radiation)-induced oxidative which pyrimidine dimers (CPD) and 6-4 photoproducts are stress in aging are discussed. the most prominent (Berneburg and Krutmann, 2000; de Journal of Investigative Dermatology Symposium Proceedings (2009) 14, Gruijl et al., 2001; Marrot and Meunier, 2008). 8–14; doi:10.1038/jidsymp.2009.6 caused by unrepaired DNA damage can be deleterious to an organism’s life functions, and the accumulation of mutations during life is thought to be a cause of aging. The link between impaired DNA repair and progeroid symptoms is under- PROGEROID SYNDROMES scored by the fact that patients with impaired NER also show Progeroid syndromes are mostly monogenetic, rare, heredi- progeroid symptoms. tary diseases, characterized by the premature development of As the DNA absorption spectrum has its peak in the UVC signs and symptoms ordinarily associated with chronic aging. and UVB range, UVA radiation as a source of DNA damage As most of the progeroid syndromes usually show only a was long neglected. Although it was shown that UVA at high limited number of features of premature aging, they are also doses would induce pyrimidine dimers (Rochette et al., called syndromes of segmental . Clinical hallmarks of 2003), UVA primarily induces oxidative DNA lesions. DNA the progeroid syndromes include mellitus, changes damage from UVA can be mediated by reactive oxygen in the volume of adipose tissue, pigmentary changes with species, primarily singlet oxygen, leading to the formation of hyper- and hypopigmentation of the skin (poikiloderma), lesions such as tyminglycols, 8oxo-guanosine, and 8oxo- regional skin fibrosis, premature hair graying or , adenosine. Nevertheless, there is an ongoing debate about , neurodegenerative symptoms, and tumors the contribution of UVA and UVA-induced DNA damage to typical of those seen in patients of older age. aging and carcinogenesis.

1Department of Dermatology, Molecular Oncology and Aging, Eberhard Karls University, Liebermeisterstrasse 25, Tu¨bingen, Germany Correspondence: Professor Dr Mark Berneburg, Molecular Oncology and Aging, Department of Dermatology, Eberhard Karls University, Liebermeisterstrasse 25, Tu¨bingen D-72076, Germany. E-mail: [email protected] Abbreviations: 8oxoG, 8oxo-guanosine; APE1, apurinic/apyrimidinic endonuclease-1; A-T, Ataxia–telangiectasia; ATM, Ataxia-telangiectasia mutated; BER, base-excision repair; CPD, cyclobutylpyrimidine dimer; CS, Cockayne syndrome; DSBR, double-strand break repair; FA, Fanconi anemia; GGR, global genome repair; HGPS, Hutchinson-Gilford progeria syndrome; hOgg, human 8-oxo-guanosineglycosylase; NER, nucleotide excision repair; TCR, -coupled repair; TTD, Trichothiodystrophy; WS, Werner syndrome; XP, Received 14 November 2008; accepted 12 January 2009

8 Journal of Investigative Dermatology Symposium Proceedings (2009), Volume 14 & 2009 The Society for Investigative Dermatology Y Kamenisch and M Berneburg Progeroid Syndromes

Genotoxic events: UV light ROS DNA damage Healthy cell is repaired correct DNA damage

DNA damage-signaling systems: Aging DNA DNA repair systems: damage is Nucleus: repaired Mitochondrion : • BER insufficient • NER • BER • DSBR • Additional and necrosis • MMR repair systems? Genomic instability

Carcinogenesis

Figure 1. The role of DNA damage in carcinogenesis and aging. DNA damage caused by genotoxic events such as or UV radiation induces DNA damage signaling systems, initiating DNA repair and regulating checkpoints and apoptosis. The genome maintenance system, which includes DNA damage signaling systems and DNA repair systems, is responsible for correct repair. If repair is erroneous, the fate of the affected cells can lead to one of three different responses. If the damage is not compatible with life, apoptosis or necrosis is initiated. Otherwise, cells can initiate aging processes, avoiding cell replication; or, if cell replication is maintained, it can lead to precancerous events.

WERNER SYNDROME (Compton et al., 2008). Additional functions in non-homo- As early as 1904, Werner syndrome (WS) was described by logous DNA-end joining, which is required not only for DNA Otto Werner, on the basis of the premature development of double-strand repair, but also for base-excision repair, have classical signs of aging (Kudlow et al., 2007). These include been suspected (Hickson, 2003; Killoran and Keck, 2006). -like, atrophic skin, a loss of subcutaneous fat The WRN may also play a role in BER, as tissue, ulceration of the skin, , premature graying, its interaction with BER has been shown (Almeida and loss of hair, osteoporosis, and diabetes and Sobol, 2007). (Thweatt and Goldstein, 1993). The risk in WS is also In WS pathogenesis, error-prone repair processes, geno- elevated (Shibuya et al., 2005). Tumors include hematologi- mic instability, and cell death caused by a dysfunctional or cal , as well as sarcomas and carcinomas of the absent WRN protein can lead to tissue dysfunction and thyroid and other organs. WS patients develop signs of , which may contribute to the aging phenotype. accelerated aging after , and they have a typical Error-prone repair, increased rates, and genomic appearance, together with thin arms and legs, a thick torso, instability could contribute to increased susceptibility to and a bird-like face. The incidence of this severe, recessive, cancer, which is also observed in this disease (Multani and autosomal disease is 1 per million individuals. The causative Chang, 2007). However, the mechanistic role of WRN in mutations are within the WRN on 8, carcinogenesis is not certain. Up- or downregulation of WRN biochemically leading to truncation, destabilization, and loss protein levels has been found in different . The WRN of the encoded WRN protein. In WS pathogenesis, two protein, which seems to be expressed ubiquitously in normal important domains of the WRN gene must be deactivated: a tissues, seems to be downregulated by epigenetic catalytically active 30-50 and an ATPase- in some tumors such as colon carcinomas (Agrelo et al., (belonging to the RecQ helicase family). Function- 2006), but upregulation of the WRN protein is also found in ally, the WRN protein is involved in DNA replication, cancer cells (Futami et al., 2008). In this context, it is homology-dependent recombination repair, and important to mention that although WRN levels can vary in maintenance. Thus, dysfunctional or absent WRN protein cancer patients with primarily functional WRN proteins, the leads to defects in and, further- increased cancer incidence in WS patients is most likely more, to genomic instability, finally resulting in cell death. because of the accumulation of DNA mutations during its The WRN protein is an important mediator in DNA DSBR. pathogenesis. DSBR can be divided into two subpathways: non-homo- logous end joining and homologous recombination repair, BLOOM SYNDROME AND ROTHMUND–THOMSON the latter requiring the presence of an identical template SYNDROME strand. Patients with Bloom syndrome are characterized by short Recently, it was shown that WRN protein oligomeres bind stature, skin photosensitivity, cafe´-au-lait macules, high- to replication forks and Holliday junctions, which are pitched voice, narrow face, , and male functionally important for homologous recombination , immunodeficiencies, chronic lung problems, and and replication at stalled or broken replication forks learning disabilities. Cancer predisposition is highly elevated

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for many types of cancer, frequently for non-Hodgkin’s of A, and the resulting protein is called . lymphoma, leukemia, and . Patients with Progerin disrupts interactions of wild-type A and B or Rothmund–Thomson syndrome are of short stature, frequently intercepts wild-type lamin A at the nuclear periphery. This exhibiting skeletal abnormalities, saddle nose, telangiectasia, could explain the abnormal nuclear morphology of HGPS juvenile cataracts, atrophic skin, hypo- and hyperpigmenta- cells (which is a reliable diagnostic marker for HGPS) and the tion (poikiloderma), and alopecia. They also have an elevated dominant inheritance of HGPS. It has also been shown in cancer predisposition, frequently experiencing not only murine models that an altered processing of Lamin A or osteogenic sarcomas but also squamous- and basal-cell expression of progerin results in a more severe HGPS-like carcinomas (Holman and Dyer, 2007). The Rothmund–Thom- phenotype than does . son syndrome is caused by defects in the RECQ4 helicase, Although HGPS cells show increased transcription whereas the genetic cause of most of the patients with Bloom after DNA damage, these cells show delayed recruitment of syndrome is impairment of the BLM gene. The tumor- DNA repair proteins and sensitivity for DNA double-strand suppressor BLM, RECQ4, and WRN belong to the breaks. It has been shown that expression of defective lamin family of RecQ , and they harbor a conserved A hinders the formation of DNA repair foci after UV domain for a 30 to 50helicase, which unwinds DNA double irradiation or cisplatin treatment (Manju et al., 2006). The strands by hydrolyzing ATP. As with the WRN helicase, the manner in which progerin interferes with DNA repair RECQ4 and the BLM helicases are necessary to maintain processes is still not known, but it would be interesting to genome integrity, but they differ in their functions and in their look for impaired NER, BER, and DSBR processes and interaction partners (Bachrati and Hickson, 2003; Killoran possible interaction of progerin with NER, BER, or DSBR and Keck, 2006). It is interesting that there is an interaction proteins. It was shown recently that expression of A-type among the tumor-suppressor proteins, FANCD2, BLM, and lamins in colorectal cancers increases the risk of death ATM. Features of cells with defective BLM or RECQ4 genes because of increased invasiveness of these tumors (Willis are abnormal DNA replication and high frequencies of et al., 2008). homologous recombination events. Functional RecQ heli- cases may be involved in facilitating removal of mutations or FANCONI ANEMIA translesional synthesis during DNA replication. Patients with Fanconi anemia (FA) are of short stature, exhibit Werner, Rothmund-Thomson, and Bloom syndromes skeletal and neurological anomalies during infancy, and have exhibit many distinct progeroid features, but all originate in an increased cancer risk (lymphoma, esophageal carcinoma dysfunctional RecQ helicases. Their common feature is an and head and neck squamous-cell carcinomas, liver, and early-onset cancer predisposition, pointing to the clinical brain tumors), but mental defects and photosensitivity are not importance of these tumor-suppressing helicases. observed (Figure 2). Commonly, FA is characterized by infantile aplastic anemia, and many patients develop HUTCHINSON–GILFORD PROGERIA SYNDROME malignancies such as acute myelogenous leukemia (Jacque- (PROGERIA INFANTUM) mont and Taniguchi, 2007). Defects in several genes may Hutchinson–Gilford progeria syndrome (HGPS) is one of the give rise to FA in an autosomal or X-linked recessive manner. most severe forms of progeria. Patients with HGPS develop All of the FA genes are involved in a DNA damage-activated signs and symptoms during their first year of life, and their mean life expectancy is 13 years, with stroke or coronary failure as the main causes of death. Like WS, symptoms of HGPS recapitulate many phenotypic signs of normal aging in an accelerated form. Symptoms of HGPS are diffuse alopecia, nail dystrophy, scleroderma-like skin changes with varied skin hyperpigmentation, loss of subcutaneous fat tissue, atherosclerosis, and rapid loss of joint mobility. There seems to be no elevated risk for tumor formation, but this could be attributed to the short life expectancy (Kudlow et al., 2007). The genetic cause of this disease lies in mutations within the LMNA gene. The gene encodes for A-type nuclear lamins, such as lamin A and lamin C, which are encoded by alternative splicing of the LMNA gene on chromosome 1. They can multimerize into filaments, and they are the main components of the nuclear lamina. Besides the function of maintaining the integrity of the nuclear lamina, they are thought to be involved in processes such as transcription, replication, cell cycle control, and cellular differentiation. Figure 2. 43-year-old female patient with Fanconi anemia and increased Most patients with HGPS have a specific mutation in chromosome instability with Mitomycin C. (a) Telangiectasia on the face and 0 11, leading to alternative splice sites at the 3 end of the (b) mild poikiloderma with hypo- and hyperpigmentation and three initial LMNA mRNA. This leads to truncation at the C terminal end squamous-cell carcinomas in the neck–chest region.

10 Journal of Investigative Dermatology Symposium Proceedings (2009), Volume 14 Y Kamenisch and M Berneburg Progeroid Syndromes

signaling pathway, which is called the FA pathway. Cells checkpoints in response to DNA damage. The latter function from FA patients are hypersensitive to DNA cross-linking can prevent chromosomal abnormalities and chromosomal agents such as cisplatin, and they show accelerated telomere instability by stopping cell cycle progress until DNA damage shortening, which is because of increased telomere breakage is repaired and thereby synchronize subsequent mitotic steps. (Grillari et al., 2007). At present, 13 different complementa- tion groups and 12 genes responsible for FA have been XERODERMA PIGMENTOSUM identified, but little is known about the function of their The rare autosomal inherited progeroid diseases to be respective gene products. Eight FA proteins form a nuclear- discussed next all have defects in the NER system. Xeroderma localized complex (FA core complex) with E3 ligase pigmentosum (XP) is characterized by extreme sun sensitivity, enzymatic activity. This ligase activity catalyzes monoubi- and all patients are highly susceptible to development of quitylation at lysine residues in target proteins. This mono- sunlight-induced cancers of the skin, with an approximate ubiquitylation does not lead to proteasomal degradation, but 1,000-fold increased risk (Figure 3). XP patients also have an it can alter cellular localization or functions of the target increased frequency of internal cancers, including central proteins. In response to DNA damage (primarily DNA nervous system cancers, and lung cancers (Berneburg et al., double-strand breaks) the FA core complex monoubiquity- 2000; Berneburg and Lehmann, 2001; Kraemer et al., 2007; lates the FA protein, FANCD2, which later co-localizes to Lim et al., 2007). Other signs include skin telangiectasia, DNA damage-associated nuclear foci, together with other ocular changes, and mental retardation. The genetic causes DNA repair proteins. As mentioned above, FA patients show of this severe disease are mutations in XP genes (XPA-XPG) an increased risk for specific cancers, which points to the (de Laat et al., 1999; de Boer and Hoeijmakers, 2000), important relationship between the FA pathway in genome leading to dysfunctional XP proteins. XP proteins are the maintenance and carcinogenesis. It is of interest that in many principal actors in the NER system (Maddukuri et al., 2007), tumors (breast cancer, cervical cancer, non-small cell lung which will be outlined below. cancer, testicular cancer, and head and neck squamous-cell Nucleotide excision repair is a versatile repair pathway carcinomas) from non-FA patients, alterations in the FA that removes bulky helix distorting DNA damage, such as pathway have also been reported (Olopade and Wei, 2003; UVC- and UVB-induced CPD and 6-4 photoproducts, as well Dhillon et al., 2004; Marsit et al., 2004; Narayan et al., 2004; as cisplatin. It has also been shown that NER is involved in Wang et al., 2006). These cancers could have had their origin in cancer predecessor cells, in which a hampered FA pathway increased mutation rates.

ATAXIA–TELANGIECTASIA Ataxia and telangiectasia (small dilated blood vessels near the surface of the skin or mucous membranes) are the eponymous signs of patients with ataxia–telangiectasia (A–T), also known as Louis–Barr syndrome. A–T patients develop ataxia, with problems in walking and standing beginning in childhood, so that most patients are bound to wheelchairs by the age of ten. A–T signs also include hypogonadism, progressive cerebellar degeneration, immunodeficiency, and sensitivity to ionizing radiation. Life expectancy is low because of a high incidence of malignancies, such as leukemia, as well as immunodefi- ciencies (Cimprich and Cortez, 2008). The genetic origin of this disease is a defect in the ATM (Ataxia–Telangiectasia Mutated) gene on . The ATM protein, a serine threonine kinase, is an important interface between DNA damage and activation of DNA repair mechanisms (Char- ames and Bapat, 2003). Cells from A–T patients are hypersensitive to DNA double-strand breaks (DSB), induced by cisplatin or g-radiation, and it is well known that ATM is involved in DSBR (Lee and Paull, 2007). Recently, it was shown that ATM is also activated by UV or reactive oxygen species treatment, leading to activation of p53 and check- point kinases, but direct involvement in NER or BER processes had not been suspected (Helt et al., 2005). However, it was shown recently that ATM can influence Figure 3. 22-year-old male patient with xeroderma pigmentosum. BER through post-translational modifications (Almeida and Poikiloderma with hypo- and hyperpigmentation, paralleled by telangiectasia Sobol, 2007). In meiosis, ATM is needed for recombination, and dry skin in sun-exposed areas. Ulcerated squamous-cell carcinoma on the and in ATM is involved in activation of cell cycle right side of nose.

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the removal of oxidative DNA damage. In this complex repair observation seems to be counterintuitive, as one would process, a several -long DNA single strand, which expect that accumulating dysfunctional NER mutations harbors the mutation, is excised, and the gap is refilled by would increase cancer susceptibility. Although this argument DNA polymerase. The NER pathway can be divided into two would seem to be conclusive, differences between XP and CS subpathways. The fast transcription-coupled repair (TCR) could be explained by the additional functions of CSA and pathway removes DNA damage from actively transcribed CSB proteins. It was shown that CSB also plays a role in basal genes, and the global genome repair (GGR) removes DNA transcription, as it can be found in complex with RNA damage from the rest of the genome. For GGR damage, polymerase II. CS cells show generally lower transcription recognition is carried out by the XPC protein in complex rates compared with CS-proficient cells, and it has been with HR23B, whereas for TCR, damage is recognized by hypothesized that transcription defects could cause the stalled RNA polymerase. Subsequent steps of NER are similar neurodegenerative features of CS (Kraemer et al., 2007). in both TCR and GGR. The XPA protein is necessary for There is also increasing evidence that CSA and CSB proteins damage verification and recruitment of further NER factors, are involved in the repair of oxidative DNA damage, either in XPB and XPD are helicases that unwind the DNA on both the BER system or in newly recognized repair systems sides of the damaged area. In subsequent steps, XPE and XPF (Frosina, 2008; Stevnsner et al., 2008). In BER, a single endonucleases excise the DNA single-strand harboring the damaged nucleotide is removed by specific enzyme com- mutation. Finally, after the DNA polymerase refills the gap, plexes. The removal of 8oxo-guanosine (8oxoG), in which and after ligation, the damaged DNA is repaired. the glycosylase 8-oxoguanosineglycosylase removes the Cells of XP patients show defects in NER, affecting TCR or damaged 8oxoG from its ribose backbone, leaving an abasic GGR or both. In XP, deficiency in the repair of direct UV- site in the DNA, is well characterized (Sung and Demple, induced DNA damage may explain the photosensitivity and 2006). In this repair process, the ribose at the abasic site is the increased skin cancer risk. In contrast, Cockayne removed, and the missing nucleotide is refilled by a specific syndrome, described below, also includes defective repair polymerase. of indirect oxidative DNA damage, which may account for its BER and NER systems are generally believed to operate stronger progeroid phenotype. separately, with each system specific for different types of UV-induced DNA damage. But recent work documents the TRICHOTHIODYSTROPHY involvement of specific proteins in the NER system during Clinical signs of trichothiodystrophy (TTD) include charac- removal of oxidative lesions specific for the BER system teristic brittle hair and nails. More severe signs are (Frosina, 2008; Stevnsner et al., 2008). This is especially neurological and skeletal degeneration, marked photosensi- certain for CSA and CSB proteins, which are involved in the tivity, growth, and mental retardation, as well as . TCR NER subpathway (Dianov et al., 1999; Tuo et al., 2003; In contrast to XP, patients with TTD do not have an increased D’Errico et al., 2007; Trapp et al., 2007; Wong et al., 2007). It risk for skin cancer, although the causative mutations can was shown that human fibroblasts of CSA- and CSB-deficient reside in the same gene (Lim et al., 2007). There are three cells are also defective in the repair of 8oxoG and different complementation groups for TTD. The majority of 8oxo-adenine (Tuo et al., 2003; D’Errico et al., 2007). patients harbor mutations in the XPD gene, in which XPD or In addition, Tuo et al. (2003) have shown that depletion of TTD or XP in combination with Cockayne syndrome (CS) can CSB proteins decreases the rate of BER-dependent repair of occur (Berneburg and Lehmann, 2001; Kraemer et al., 2007). 8 oxoG, further indicating that BER-specific hOgg (human The second group has mutations in the XPB gene. The third 8-oxoGuanosineglycosylase) and CSB might act as a com- group shows a temperature sensitive instability of the mon protein complex. Furthermore, Wong et al. transcription factor TFIIH. (2007) showed that BER-associated apurinic/apyrimidinic endonuclease (APE1) interacts with the CSB protein. In COCKAYNE SYNDROME Ogg1-deficient mice, repair of 8oxoG is impaired (Arai Cockayne syndrome is characterized by mental and devel- et al., 2002), as CSB-deficient mice show age-dependent opmental retardation and photosensitivity. Other signs are accumulation of 8oxoG and other oxidative DNA lesions. progressive sensorineural hearing loss, short stature, a typical However, in mice deficient in Ogg1 and CSB, 8oxoG bird-like face, deep-set , loss of subcutaneous fat, and accumulation is much higher, strengthening the link between progressive neurological degeneration. Patients show signs of BER-associated Ogg1 and NER-associated CSB protein. Not progressive aging and suffer from progressive neurodegenera- only do TCR-associated NER proteins such as CSA and CSB tion, with demyelinization of the brain stem and cerebellum seem to have additional functions in the repair of oxidative (Berneburg and Lehmann, 2001). There are two complemen- DNA damage but so also does the GGR-associated NER tation groups in CS: CSA and CSB, but specific mutations in protein XPC, as has been shown in the work of Kassam and the XPB-, XPD- and XPG-genes can also cause a CS Rainbow (2007). phenotype (Berneburg et al., 2000; Berneburg and Lehmann, Therefore, as described above, the discovery of new roles 2001; Kraemer et al., 2007; Lim et al., 2007). Cells from CS for the CS proteins in other repair pathways, such as the patients are characterized by impaired TCR. Unlike XP cells, repair of oxidative stress, may help to differentiate among the which also can have defects in the TCR subpathway, the pathways that lead to either carcinogenesis on the one hand cancer incidence in CS patients is not elevated. This or aging on the other.

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CONCLUSION Dhillon VS, Shahid M, Husain SA (2004) CpG methylation of the FHIT, Progeroid syndromes are a heterogeneous group of diseases FANCF, cyclin-D2, BRCA2 and RUNX3 genes in Granulosa cell tumors with overlapping features of accelerated aging. Problems in (GCTs) of ovarian origin. Mol Cancer 3:33 genome maintenance caused by impairment in the function Dianov G, Bischoff C, Sunesen M, Bohr VA (1999) Repair of 8-oxoguanine in DNA is deficient in Cockayne syndrome group B cells. Nucleic Acids of different genes are responsible for the clinical features of Res 27:1365–8 these diseases. Owing to mutations in these genes, important Frosina G (2008) Oxidatively damaged DNA repair defect in cockayne functions of genome maintenance, including repair systems, syndrome and its complementation by heterologous repair proteins. Curr such as DSBR, NER, and BER as well as DNA damage Med Chem 15:940–53 signaling, are impaired. Cancer predisposition and early Futami K, Ishikawa Y, Goto M, Furuichi Y, Sugimoto M (2008) Role of Werner onset of aging are clinical features of most of the progeroid syndrome gene product helicase in carcinogenesis and in resistance to genotoxins by cancer cells. Cancer Sci 99:843–8 syndromes, but the highly increased frequency of skin cancer Grillari J, Katinger H, Voglauer R (2007) Contributions of DNA interstrand in the NER-deficient disease, XP, points to the importance of cross-links to aging of cells and organisms. Nucleic Acids Res this repair system for UV-induced skin cancer. On the other 35:7566–76 hand, NER-deficient diseases such as CS and TTD do not Helt CE, Cliby WA, Keng PC, Bambara RA, O’Reilly MA (2005) Ataxia–te- show increased photocarcinogenesis. 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