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Published in final edited form as: Mech Ageing Dev. 2008 Feb 3;129(7-8):492–497. doi: 10.1016/j.mad.2008.01.005

Clinical implications of the basic defects in Cockayne Syndrome and xeroderma pigmentosum and the DNA lesions responsible for cancer, neurodegeneration and aging

JE Cleaver 1, I Revet 1
PMCID: PMC2517418  NIHMSID: NIHMS57857  PMID: 18336867

Abstract

Cancer, aging, and neurodegeneration are all associated with DNA damage and repair in complex fashions. Aging appears to be a cell and tissue-wide process linked to the insulin-dependent pathway in several DNA repair deficient disorders, especially in mice. Cancer and neurodegeneration appear to have complementary relationships to DNA damage and repair. Cancer arises from surviving cells, or even stem cells, that have down-regulated many pathways, including apoptosis, that regulate genomic stability in a multi-step process. Neurodegeneration however occurs in nondividing neurones in which the persistence of apoptosis in response to reactive oxygen species is, itself, pathological. Questions that remain open concern: sources and chemical nature of naturally occurring DNA damaging agents, especially whether mitochondria are the true source; the target tissues for DNA damage and repair; do the human DNA repair deficient diseases delineate specific pathways of DNA damage relevant to clinical outcomes; if naturally occurring reactive oxygen species are pathological in human repair deficient disease, would anti-oxidants or anti-apoptotic agents be feasible therapeutic agent?

Introduction

DNA repair deficiencies have been linked to three major clinical outcomes: cancer, neurodegeneration and aging. Each outcome is associated with different combinations of pathways of DNA damage and repair, and with a corresponding different set of human hereditary diseases. The human repair deficient diseases xeroderma pigmentosum (XP) and Cockayne syndrome (CS) have specific phenotypes of cancer and neurodegeneration, but their relationship to premature aging is not clear, although their fibroblasts do not senesce prematurely in vitro (Cleaver, 1984). XP patients have not been followed in sufficient numbers to know whether they age prematurely, apart from their cancer burden. CS patients show a neurological and developmental degeneration that differs from normal aging, but is described as a segmental progeroid (Nance and Berry, 1992). Cancer, neurodegeneration and aging are therefore different pathological outcomes of repair deficiencies that will require different therapeutic approaches.

Most DNA repair deficiencies result in some form of cancer, if not in human then in the corresponding mouse mutants, as was evident from the earliest association of nucleotide excision repair (NER) with skin cancer in XP (Cleaver, 1968; Cleaver, 1969; Friedberg et al., 1998). Human diseases that link DNA repair to cancer include: mismatch repair (MMR) associated with colon cancer; human patients with mutations in MUTYH and mice that have both Mutyh and Ogg1 deleted are predisposed to colorectal cancer (David et al., 2007); DNA double strand break (DSB) repair with lymphomas in ataxia telangiectasia (AT) and related disorders (Barzilai et al., 2002); NER with skin cancer in XP (Cleaver and Mitchell, 2005); homologous recombination with breast cancer through the familial breast cancer genes BRCA1 and Fanconi anemia (FANCD1/BRCA2) genes (McKinnon and Caldecott, 2007); crosslink repair with leukemia in Fanconi anemia (FANC) genes (McKinnon and Caldecott, 2007).

What are the sources and chemical nature of naturally occurring DNA damaging agents?

The default explanation for DNA damage from endogenous sources is that reactive oxygen species (ROS) from mitochondrial leakage is the major culprit (Wallace, 2005). A direct test of a mitochondrial source for nuclear damage, however, failed to support the idea (Hoffmann et al., 2004). The question remains whether mitochondrial ROS themselves, or longer-lived products such as oxidized proteins, lipids, sugars and nitroso compounds migrate sufficiently to reach the nuclear DNA. ROS include an exceedingly complex spectrum of products, many at low concentrations in many different classes of macromolecules (Barzilai et al., 2002). ROS generate many singly modified bases such as 7,8-dihydro-8-oxoguanine (8-oxo-G) that are substrates for base excision repair (BER) (David et al., 2007), and oxidized purine products (5′,8-purine cyclodeoxynucleosides) that require NER for their repair and block transcription (Brooks et al., 2000; Kuraoka et al., 2001). Lipid oxidation products produce malondialdehyde-deoxyguanosine (M-1-dG) adducts in DNA that block transcription (Cline et al., 2004). Analysis in a cell-free system showed that although UV-induced pyrimidine dimers and single strand breaks (SSBs) were effective blocks to transcription, base damage of the kind subject to BER were not (Kathe et al., 2004).

ROS plays important signaling functions in inflammation and neural signaling. Cellular responses to ROS may therefore represent a delicate balance between the production of necessary ROS for tissue growth and differentiation, the suppression of excess ROS by antioxidants such as glutathione and catalase, and repair of ROS-induced DNA damage. In S cerevisiae, for example, different oxidizing agents require different, almost non-overlapping, sets of genes for resistance, few of which represent DNA repair genes (Birrell et al., 2001; Game et al., 2003; Thorpe et al., 2004). Due to the complexity of cellular sources of ROS, and their potential involvement in normal cell signaling processes, the relative sensitivity of various genetic disorders to a range of oxidizing agents is still unclear.

Variations in the severity of CS symptoms between patients have not yet been related to the sites of mutation, and complete loss of CSB results in a milder phenotype than many point mutations (Horibata et al., 2004). The presence of mutant misfolded CSA or B proteins might therefore be as important in CS as protein aggregates are in other neurological diseases (Ciechanover and Brundin, 2003). Variations could also occur in cellular antioxidants or ROS production by different mitochondrial haplotypes (Wallace, 2005). CSB protein functions in chromatin remodeling (Newman et al., 2006); CSA & B are required for ubiquitylation of RNA pol II (Lee et al., 2002); CSA is a cofactor for E3 ubiquitylation ligase that may target many proteins (Groisman et al., 2003). These many additional functions could also contribute to the range of clinical symptoms.

DNA damage and repair in aging?

Aging has been variously associated with many parameters, but there may be subtle differences between life-span, that is genetically determined and is species specific, and aging that is associated with functional decline in various tissues often associated with pathologies such as cancer. The insulin-dependent growth factor pathway (IGF-1/GH) plays an important role in energy metabolism and life-span in many species (Hansen et al., 2005). Although the basal metabolic rate would consequently be expected to cause variations in ROS, no influence on spontaneous mutagenesis could be detected (Lanfear et al., 2007). An RNAi screen in C elegans for genes that regulate life-span generated many genes in endocrine and metabolic pathways but few DNA repair genes (Hansen et al., 2005). Even so, DNA repair does seem to be rate limiting for stem cell renewal in the hematopoeitic system, due to accumulation of unrepaired damage while in the quiescent state (Rossi et al., 2007a; Rossi et al., 2007b).

Several repair deficient diseases show deficiencies in the IGF-1/GH axis: the Xp-d mouse with the human trichothiodystrophy (TTD) mutation (de Boer et al., 2002), knockouts in the 5′ NER nuclease Xpf and Ercc1 (Niedernhofer et al., 2006), and Csb (van der Pluijm et al., 2006). This may represent unrepaired damage to specific tissues such as liver and pancreas. The first DNA repair knockout was in Ercc1 in which the liver showed evidence of DNA damage and elevated p53 levels (McWhir et al., 1993). A critical decline in the p53 response to DNA damage with age has recently been shown (Feng et al., 2007), but here as in so many examples the question remains which is the cause and which is the consequence of the aging process.

DNA damage and repair in neurodegeneration

Three groups of repair deficient disease have distinctive neurodegenerative phenotypes: the NER diseases of XP and CS, the cerebellar ataxias associated with SSB repair, and diseases associated with DSB repair and damage-dependent signaling (Table 1) (McKinnon and Caldecott, 2007). These all appear to be recessive conditions that show wide ranges of clinical severity even within a single disease. Parents have few reported symptoms, implying that the relevant repair systems in normal individuals have excess capacity for dealing with endogenous levels of damage. Premature aging is featured in individual diseases among all of these classes, showing no consistent mechanism relating DNA damage to aging. These classes all appear to share common elements of degeneration of the central nervous system especially the cerebellum and Purkinje cells (Kohji et al., 1998; Hayashi, 1999; Hayashi et al., 2001; Cleaver, 2005; Hayashi et al., 2005; Laposa et al., 2007a; McKinnon and Caldecott, 2007) that show high sensitivity to oxidative damage (Leech et al., 1985; Otsuka and Robbins, 1985; Barlow et al., 1999; Hayashi et al., 2001; Sun et al., 2001; Reichenbach et al., 2002; Chen et al., 2003; de Waard et al., 2003; Goldbaum and Richter-Landsberg, 2004; Liu et al., 2006).

Table 1.

Major diseases of DNA repair, the repair pathways and pathology

DNA repair pathways1 Syndrome and common abbreviation2 Gene name3 Phenotype
GGR/NER Xeroderma pigmentosum (XP) XPE
XPC

  • -Photosensitivity

  • -Skin cancer
NER common pathway Xeroderma pigmentosum (XP) XPA
XPB
XPD
XPF
XPG

  • -Cerebellar degeneration

  • -Photosensitivity

  • -Skin cancer
NER common pathway Trichothiodystrophy (TTD) XPB
XPD
TFB5

  • -Photosensitivity

  • -Hair and immune deficiency

  • -Life-shortening (mouse)
Bypass polymerase Xeroderma pigmentosum variant (XPV) Pol eta

  • -Photosensitivity

  • -Skin cancer
TCR Cockayne syndrome (CS) CSA
CSB

  • -Retinal, cerebellar (purkinje), ganglial calcifications,

  • -Aging
TCR UV sensitive syndrome (UVs) CSB

  • -Mild photosensitivity
TCR Cerebro-oculo-facio-skeletal syndrome (COFS) ERCC1
CSB

  • -Severe neonatal lethal developmental disorder
BER Ataxia-oculomotor apraxia syndrome (AOA) APTX

  • -Cerebellar ataxia

  • -Oculomotor apraxia
Topoisomerase-1 induced breaks (TCR) Spinocerebellar ataxia with axonal neuropathy (SCAN1) TDP1

  • -Postmitotic neurons (cerebellar ataxia and axonal neuropathy)
NHEJ and V(D)J recombination Severe combined immunodeficiency with sensitivity to ionizing radiation (RS-SCID) DCLRE1C

  • -Immunodeficiency

  • -Photosensitivity
NHEJ LIG4 syndrome (LIG4) LIG4

  • -Microcephaly

  • -Lymphoreticular disease

  • -Immunodeficiency
NHEJ Severe combined immunodeficiency with microcephaly (SCID) NHEJ1

  • -Microcephaly

  • -Immunodeficiency

  • -Growth retardation

  • -Photosensitivity
BER Werner syndrome (WRN) WRN

  • -Premature aging

  • -Premature arteriosclerosis

  • -Diabetes mellitus

  • -Scleroderma-like skin changes
DSB repair and signal transduction Ataxia telangiectasia (AT) ATM

  • -Cerebellar ataxia

  • -Oculomotor apraxia

  • -lymphocytic leukemia
DSB repair and signal transduction Ataxia-telangiectasia-like disorder (ATLD) MRE11

  • -Cerebellar ataxia

  • -Oculomotor apraxia
DSB repair and signal transduction Nijmegen breakage syndrome (NBS) NBS1

  • -Microcephaly,

  • -Growth retardation

  • -Immunodeficiency

  • -Cancer predisposition
ATR signaling pathway Seckel syndrome 1 (SCKL1) ATR
SCKL2
SCKL3

  • -Microcephaly

  • -Growth retardation

  • -Mental retardation
ATR signaling pathway Microcephaly primary autosomal recessive 1 (MCPH1) MCPH1
MCPH2
MCPH4

  • -Microcephaly
NHEJ and V(D)J recombination Inactivation of Ku70 or Ku80 in mouse models Ku70
Ku80

  • -Premature aging

  • -Cancer predisposition

  • -Lymphomas
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1

Abbreviations not already defined in the text include: ATM, ataxia telangiectasia mutated; ATR, ataxia telangiectasia mutated and Rad3-related; NHEJ, nonhomologous end joining; V(D)J, regions of the immunoglobulin locus involved in rearrangements.

2

Abbreviations shown in parenthesis represent the common abbreviations for each disease. Ku70, Ku80 are two end binding proteins associated with DSB repair.

3

The initials represent the common designations for each gene(s) involved in the corresponding disease.

Recent studies have shown that differentiation of neurons is associated with up-regulation of ROS and down-regulation of antioxidants (Tsatmali et al., 2005). This would put a heavier demand on cells’ capacity to repair ROS damage during differentiation, just when a reduction of overall NER appears also to occur (Nouspikel and Hanawalt, 2000). There is some evidence that premature entry of neuronal cells into the cell cycle can trigger cell death (Herrup et al., 2004; Kruman, 2004) by a mechanism involving recruitment of Pol beta instead of replicative polymerases (Copani et al., 2007), which would be exacerbated by unrepaired neuronal damage (Nouspikel and Hanawalt, 2003). No evidence for premature DNA replication was found in a mouse model of Cs-b with severe neurodegeneration (Laposa et al., 2007a). There remains, however, limited knowledge of repair systems in specific areas of the brain, in contrast to other models of differentiation (Nouspikel and Hanawalt, 2000; Nouspikel and Hanawalt, 2006).

Do the human DNA repair deficient diseases delineate specific subsets of DNA damage relevant to clinical outcomes?

A self-evident observation is that cancer arises in tissues with proliferative potential, whereas neurodegeneration occurs in post-mitotic brain tissue. Therefore a unifying principle for damage-dependent neurodegeneration would be the prediction that deficits in TCR and SSB repair should lead to increased apoptosis of post-mitotic neurons, especially since single strand breaks are also transcription blocking lesions (Kathe et al., 2004). Neurodegeneration might be ascribed to the greater relative importance of a TCR-like repair in differentiated brain cells such that a failure of TCR triggers an apoptotic response (Ljungman and Zhang, 1996; Proietti De Santis et al., 2002; D’Errico et al., 2003). Increased apoptosis has been demonstrated for TCR deficits (Ljungman and Zhang, 1996). Since apoptosis would remove damaged cells from the skin in CS patients this phenotype would, conversely, prevent UV carcinogenesis (D’Errico et al., 2005).

Neurodegeneration appears to be mainly associated with TCR deficits and GGR deficits more extensively with cancer (Cleaver, 2005). A recent suggestion that RNA pol II is a universal sensor of DNA damage (Lindsey-Boltz and Sancar, 2007) blurs the distinction between TCR and global repair. The neurological symptoms of CS patients have been ascribed to defective repair in the brain of endogenous oxidative damage that blocks transcription (Kuraoka et al., 2000; Osterod et al., 2002; de Waard et al., 2003; Kyng et al., 2003; Tuo et al., 2003; Cline et al., 2004), but the more common oxidative base damages (8-oxo-G, 5-hydroxycytosine, thymine glycols) do not block transcription and are therefore not the culprits in neurodegeneration (Kathe et al., 2004). CSA and CSB cells are however different in their responses to oxidative damage, despite overlap in clinical symptoms (de Waard et al., 2004; D’Errico et al., 2007). The oxidative lesion 8-oxo-G does not appear to accumulate in CS autopsy material (Hayashi et al., 2005) despite the higher amounts of protein oxidation and lipid oxidation in the brains of CS patients (Hayashi et al., 2001) and crossing Cs-b mice with Ogg1 deficient mice did not enhance the neurological symptoms (Laposa et al., 2007b). Surprising is the absence of reported neurological or aging phenotypes among mouse strains lacking glycosylases which are the recognition and excision enzymes for BER that would be expected to show increased sensitivity to ROS (Friedberg et al., 1998), although many oxidative base damages are not transcription blocking lesions (Kathe et al., 2004). Perhaps these strains should be screened more carefully, or combined strains made lacking several glycosylases to increase the chances of detecting such a phenotype.

Most XP-E, XP-C or XP-V patients do not have clinically reported neurodegeneration, and evidence for life-shortening is difficult to obtain due to the profound influence of wide variations in solar exposure and clinical care. There is one report of an XP-C patient with autism (Khan et al., 1998) and one of an XP-V patient with neurological symptoms (Hessel et al., 1992), but neurological symptoms in these groups are rare. XPE and XPC are mainly involved in damage recognition in nontranscribing DNA and XPV/Pol eta in replicating damaged DNA. Therefore loss of these functions should have little impact on differentiated brain tissue that is predominantly nondividing and heavily dependent on TCR. Crossing Cs-b mice with Xp-c mice, however, strongly enhanced the neurological symptoms showing that XPC is not without some relevance to neurological maintenance (Laposa et al., 2007b). Some evidence suggests that XPC is required for repair of oxidative damage that might be necessary in the brain (Kassam and Rainbow, 2007). The WRN protein, a helicase defective in the specific aging disorder Werners syndrome facilitates replicative bypass by Pol eta (Kamath-Loeb et al., 2007), so some association of the XP-V and Werners phenotypes could be expected to impact lifespan.

These considerations suggest that the presently unidentified causative DNA lesions for neurodegeneration should be strong transcription blocks, but poorer substrates for NER, BER or blocks to the replicative polymerases (Cleaver, 2005).

What constitutes feasible therapeutic targets?

The critical question is whether, now that we have extensive knowledge of the molecular biology and genetics of the repair deficient diseases, does this help the patients? One simple approach that did not need extensive basic research is for XP patients to reduce their skin cancer risks by avoiding sun exposure, although even here there is still uncertainty as to how rigorous this needs to be and the relative roles of UVA and UVB and the contribution of competing reactions such as production of vitamin D (Garland et al., 1990; Weinstock et al., 1992) that is reported to increase NER efficiency (Gupta et al., 2007). A recent example of the role of protection is seen in a Guatemalan population with a founder XPC mutation in which limited sun protection and clinical care results in death around the age of 10, whereas similar XPC mutations have much less influence on lifespan in the US (Cleaver et al., 2007).

Neurodegeneration is a more difficult matter. Consideration of the large number of potential protein targets of the ATM, ATR and CHK2 kinases, the possibility of identifying clinically relevant targets is daunting (Smolka et al., 2007). Several potential points of attack are conceivable: premature entry into the cell cycle, the proteasomal pathway, apoptosis and ROS. Each of these has been investigated in model systems with various degrees of success, but few have yet emerged from clinical trials as strong candidates. The strongest evidence for a biological role for ROS comes from treatment of mice with antioxidants that have achieved life extension as well as reduced neurodegeneration (Heidrick et al., 1984; Holloszy, 1998; Meydani et al., 1998). Treatment of Atm mice with antioxidants has shown promising success in reducing Purkinje cell damage and improving behavioral endpoints (Chen et al., 2003; Gueven et al., 2006). Another option would be the use of anti-apoptotic or cell-cycle arresting agents, although the persistence of cells with oxidative damage might lead to a different form of pathology.

The neurodegenerative symptoms in mice are generally milder than in human and the cancer burden higher, especially for Cs (van der Horst et al., 1997; van der Horst et al., 2002; Laposa et al., 2007b) and Xpa (Berg et al., 1997; De Vries, 1997; Tanaka et al., 2001). Variations due to strain backgrounds are also factors, especially regarding life-shortening versus cancer risk (Li et al., 2007; Partridge and Gems, 2007). The Cs-b strain that has been most extensively used (van der Horst et al., 1997; Laposa et al., 2007b) contains a truncation mutation that may resemble the mild human UV-sensitive disorder associated with an early truncation in CSB that lacks neurodegeneration (Horibata et al., 2004), unlike most CSB patients with amino acid changes and termination mutations scattered throughout the gene. There is consequently a need for further mouse models especially those that recapitulate the mutations causing severe CS clinical disorders.

There is a major regulatory hurdle that needs to be faced regarding clinical trials in human repair deficient patients. There are so few patients that trials are almost impossible to design to satisfy safety and effectiveness criteria. The difficulties experienced with development of a DNA repair cream for skin cancer in XP patients (Yarosh et al., 2001) exemplifies the difficulties facing treatment of complex disorders of neurodegeneration in rare patients. One possibility would be to test drugs and antioxidants that have already been approved by FDA for use in Alzheimers, Parkinson’s and other more common neurological disorders. Developing therapeutic approaches is most challenging when translating bench knowledge to patients’ benefit.

Acknowledgments

We are grateful to the Luke O’Brien Foundation whose continued support and encouragement was instrumental in furthering our work on Cockayne Syndrome, and the XP Society, Poughkeepsie, NY for their support of our work on XP. The work described here was also supported in part by grants from the National Institutes of Neurological Disorders and Stroke grant 1R01NS052781 (JEC), and the Cancer Center Support grant P30 CA82103 (PI: McCormick).

Footnotes

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References

  1. Barlow C, Dennery PA, Shigenaga MK, Smith MA, Morrow JD, Roberts LJI, Wynshaw-Boris A, Levine RL. Loss of the ataxia-telangiectasia gene product causes oxidative damage in target organs. Proc Natl Acad Sci U S A. 1999;96:9915–9919. doi: 10.1073/pnas.96.17.9915. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Barzilai A, Rotman G, Shiloh Y. ATM deficiency and oxidative stress: a new dimension of defective response to DNA damage. DNA Repair. 2002;1:3–25. doi: 10.1016/s1568-7864(01)00007-6. [DOI] [PubMed] [Google Scholar]
  3. Berg RJW, Vries Ad, Steeg HvGruijl FRd. Relative susceptibilities of XPA knockout mice and their heterozygous and wild-type littermates to UVB-induced skin cancer. Cancer Research. 1997;57:581–584. [PubMed] [Google Scholar]
  4. Birrell GW, Giaever G, Chu AM, Davis RW, Brown JM. A genome-wide screen in Saccharomyces cerevisiae for genes affecting UV radiation sensitivity. Proc Natl Acad Sci U S A. 2001;98:12608–12613. doi: 10.1073/pnas.231366398. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Brooks PJ, Wise DS, Berry DA, Kosmoski JV, Smerdon MJ, Somers RL, Mackie H, Spoonde AY, Ackerman EJ, Coleman K, Tarone RE, Robbins JH. The oxidative DNA lesion 8,5′-(S)-cyclo-2′-deoxyadenosine is repaired by the nucleotide excision repair pathway and blocks gene expression in mammalian cells. J Biol Chem. 2000;275:22355–22362. doi: 10.1074/jbc.M002259200. [DOI] [PubMed] [Google Scholar]
  6. Chen P, Peng C, Luff J, Spring K, Watters D, Bottle S, Furuya S, Lavin MF. Oxidative stress is responsible for deficient survival and dendritogenesis in purkinje neurons from ataxia-telangiectasia mutated mutant mice. J Neurosci Res. 2003;23:11453–11460. doi: 10.1523/JNEUROSCI.23-36-11453.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Ciechanover A, Brundin P. The ubiquitin proteasome system in neurodegenerative diseases: sometimes the chicken, sometimes the egg. Neuron. 2003;40:427–446. doi: 10.1016/s0896-6273(03)00606-8. [DOI] [PubMed] [Google Scholar]
  8. Cleaver JE. Defective repair replication in xeroderma pigmentosum. Nature. 1968;218:652–656. doi: 10.1038/218652a0. [DOI] [PubMed] [Google Scholar]
  9. Cleaver JE. Xeroderma pigmentosum: a human disease in which an initial stage of DNA repair is defective. Proceedings of the National Academy of Sciences USA. 1969;63:428–435. doi: 10.1073/pnas.63.2.428. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Cleaver JE. DNA repair deficiencies and cellular senescence are unrelated in xeroderma pigmentosum cell lines. Mechanisms of Aging and Development. 1984;27:189–196. doi: 10.1016/0047-6374(84)90044-7. [DOI] [PubMed] [Google Scholar]
  11. Cleaver JE. Cancer in xeroderma pigmentosum and related disorders of DNA repair. Nature reviews on cancer. 2005;5:564–573. doi: 10.1038/nrc1652. [DOI] [PubMed] [Google Scholar]
  12. Cleaver JE, Feeney L, Tang JY, Tuttle P. Xeroderma pigmentosum group C in an isolated region of Guatemala. J Invest Dermatol. 2007;127:493–496. doi: 10.1038/sj.jid.5700555. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Cleaver JE, Mitchell DL. Ultraviolet Radiation Carcinogenesis. In: Bast RJ, Kufe DW, Pollock RE, Weichselbaum RW, Holland JF, Frei E III, editors. Cancer Medicine. BC Deckker Inc; 2005. [Google Scholar]
  14. Cline SD, Riggins JN, Tornaletti S, Marnett LJ, Hanawalt PC. Malondialdehyde adducts in DNA arrest transcription by T7 RNA polymerase and mammalian RNA polymerase II. Proc Nat Acad Sci USA. 2004;101:7275–7280. doi: 10.1073/pnas.0402252101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Copani A, Caraci F, Hoozemans JJM, Calafiore M, Sortino MA, Nicoletti F. The nature of the cell cycle in neurons: focus on a “non-canonical” pathwayof DNA replication causally related to cell death. Biochim Biophys Acta. 2007;1772:409–412. doi: 10.1016/j.bbadis.2006.10.016. [DOI] [PubMed] [Google Scholar]
  16. D’Errico M, Parlanti E, Teson M, Degan P, Lemma T, Calcagnile A, Iavarone I, Jaruga P, Ropolo M, Pedrini AM, Orioli D, Frosina G, Zambruno G, Dizdaroglu M, Stefanini M, Dogliotti E. The role of CSA in the response to oxidative DNA damage in human cells. Oncogene. 2007 doi: 10.1038/sj.onc.1210232. Epub ahead of print. [DOI] [PubMed] [Google Scholar]
  17. D’Errico M, Teson M, Calcagnile A, Nardo T, De Luca N, Lazzari C, Soddu S, Zambruno G, Stefanini M, Dogliotti E. Differential role of transcription-coupled repair in UVB-induced response of human fibroblasts and keratinocytes. Cancer res. 2005;65:432–438. [PubMed] [Google Scholar]
  18. D’Errico M, Teson M, Calcagnile A, Proietti De Santis L, Nikaido O, Botta E, Zambruno G, Stefanini M, Dogliotti E. Apoptosis and efficient repair of DNA damage protect human keratinocytes against UVB. Cell Death Differ. 2003;10:754–756. doi: 10.1038/sj.cdd.4401224. [DOI] [PubMed] [Google Scholar]
  19. David SS, O’Shea VL, Kundu S. Base-excision of oxidative DNA damage. Nature. 2007;447:941–950. doi: 10.1038/nature05978. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. de Boer J, Andressoo JO, de Wit J, Huijmans J, Beems RB, van Steeg H, Weeda G, van der Horst GTJ, van Leeuwan W, Themmen APN, Meradji M, Hoeijmakers JHJ. Premature aging in mice deficient in DNA repair and transcription. Science. 2002;296:1276–1279. doi: 10.1126/science.1070174. [DOI] [PubMed] [Google Scholar]
  21. De Vries A. Carcinogenesis in XPA-deficient mice. Department of Immunology; Utrecht: 1997. [Google Scholar]
  22. de Waard H, de Wit J, Andressoo JO, van O, Oostrom CT, Riis B, Weimann A, Poulsen HE, cvan Steeg H, Hoejmakers JH, van der Horst GH. Different effects of CSA and CSB deficiency on sensitivity to oxidative damage. Mol Cell Biol. 2004;24:7941–7948. doi: 10.1128/MCB.24.18.7941-7948.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. de Waard H, de Wit J, Gorgels TG, van den Aardweg G, Andressoo JO, Vermeij M, van Steeg H, Hoeijmakers JH, van der Horst GT. Cell type-specific hypersensitivity to oxidative damage in CSB and XPA mice. DNA Repair (Amst) 2003;2:13–25. doi: 10.1016/s1568-7864(02)00188-x. [DOI] [PubMed] [Google Scholar]
  24. Feng Z, Hu W, Teresky AK, Hernando E, Cordon-Cardo C, Levine AJ. Declining p53 function in the aging process: A possible mechanism for the increased tumor incidence in older populations. Proc Natl Acad Sci USA. 2007;104:16633–16638. doi: 10.1073/pnas.0708043104. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Friedberg EC, Meira LB, Cheo DL. Database of mouse strains carrying targeted mutations in genes affecting cellular responses ot DNA damage. Version 2. Mutation Research. 1998;407:217–226. doi: 10.1016/s0921-8777(97)00066-9. [DOI] [PubMed] [Google Scholar]
  26. Game JC, Birrell GW, Brown JA, Shibata T, Baccari C, Chu AM, Williamson MS, Brown JM. Use of a genome-wide approach to identify new genes that control resistance of Saccharomyces cerevisiae to ionizing radiation. Radiat Res. 2003;160:14–24. doi: 10.1667/rr3019. [DOI] [PubMed] [Google Scholar]
  27. Garland FC, Garland CF, Gorham ED, Young JF. Geographic variation in breast cancer mortality in the United States: a hypothesis involving exposure to solar radiation. Prev Med. 1990;19:614–622. doi: 10.1016/0091-7435(90)90058-r. [DOI] [PubMed] [Google Scholar]
  28. Goldbaum O, Richter-Landsberg C. Proteolytic stress causes heat shock protein induction, tau ubiquitination, and the recruitment of ubiquitin to tau-positive aggregates in oligodendrocytes in culture. J Neurosci. 2004;24:5748–5757. doi: 10.1523/JNEUROSCI.1307-04.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Groisman R, Polanowski J, Kuraoka I, Sawada J-I, Saijo M, Drapkin R, Kisselev AF, Tanaka K, Nakatani Y. The ubiquitin ligase activity in the DDB2 and CSA complexes is differentially regulated by the COP9 signalosome in response to DNA damage. Cell. 2003;113:357–367. doi: 10.1016/s0092-8674(03)00316-7. [DOI] [PubMed] [Google Scholar]
  30. Gueven N, Luff J, Peng C, Hosokawa K, BottleSLavin MF. Dramatic extension of tumor latency and correction of neurobehavioral phenotype in Atm-mutant mice with a nitroxide antioxidant. Free Radic Biol Med. 2006;41:992–1000. doi: 10.1016/j.freeradbiomed.2006.06.018. [DOI] [PubMed] [Google Scholar]
  31. Gupta R, Dixon KM, Deo SS, Holliday CJ, Slater M, Halliday GM, Reeve VE, Mason RS. Photoprotection by 1,25 dihydroxyvitamin D3 is associated with an increase in p53 and a decrease in nitric oxide products. J Invest Dermatol. 2007;127:707–715. doi: 10.1038/sj.jid.5700597. [DOI] [PubMed] [Google Scholar]
  32. Hansen M, Hsu AL, Dillin A, Kenyon C. New genes tied to endocrine, metabolic, and dietary regulation of lifespan from a Caenorhabditis elegans genomic RNAi screen. PLoS Genet. 2005;1:119–128. doi: 10.1371/journal.pgen.0010017. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Hayashi M. Apoptotic cell death in child-onset neurodegenerative disorders. No To Hattatsu. 1999;31:146–152. [PubMed] [Google Scholar]
  34. Hayashi M, Araki S, Kohyama J, Shioda K, Fukatsu R. Oxidative nucleotide damage and superoxide dismutase expression in the brains of xeroderma pigmentosum group A and Cockayne syndrome. Brain Dev. 2005;27:34–38. doi: 10.1016/j.braindev.2004.04.001. [DOI] [PubMed] [Google Scholar]
  35. Hayashi M, Itoh M, Araki S, Kumada S, Shioda K, Tamagawa K, Mizutani T, Morimatsu Y, Minagawa M, Oda M. Oxidative stress and disturbed glutamate transport in hereditary nucleotide repair disorders. J Neuropathol Exp Neurol. 2001;60:350–356. doi: 10.1093/jnen/60.4.350. [DOI] [PubMed] [Google Scholar]
  36. Heidrick ML, Hendricks LC, Cook DE. Effect of dietary 2-mercaptoethanol on the life span, immune system, tumor incidence and lipid peroxidation damage in spleen lymphocytes of aging BC3F1 mice. Mech Ageing Dev. 1984;27:341–358. doi: 10.1016/0047-6374(84)90057-5. [DOI] [PubMed] [Google Scholar]
  37. Herrup K, Neve R, Ackerman SL, Copani A. Divide and die:cell cycle events thas triggers of nerve cell death. J Neurosci. 2004;24:9232–9239. doi: 10.1523/JNEUROSCI.3347-04.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Hessel A, Siegel RJ, Mitchell DL, Cleaver JE. Xeroderma pigmentosum variant with multisystem involvement. Archives of Dermatology. 1992;128:1233–1237. [PubMed] [Google Scholar]
  39. Hoffmann S, Spitkovsky D, Radicella JP, Epe B, Wiesner RJ. Reactive oxygen species derived from the mitochondrial respiratory chain are not responsible for the basal levels of oxidative base modifications observed in nuclear DNA of Mammalian cells. Free Radic Biol Med. 2004;36:765–773. doi: 10.1016/j.freeradbiomed.2003.12.019. [DOI] [PubMed] [Google Scholar]
  40. Holloszy JO. Longevity of exercising male rats: effect of an antioxidant supplemented diet. Mech Ageing Dev. 1998;100:211–219. doi: 10.1016/s0047-6374(97)00140-1. [DOI] [PubMed] [Google Scholar]
  41. Horibata K, Iwamoto Y, Kuraoka I, Jaspers NG, Kurimasa A, Oshimura M, Ichihashi M, Tanaka K. Complete absence of Cockayne syndrome group B gene product gives rise to UV-sensitive syndrome but not Cockayne syndrome. Proc Natl Acad Sci USA. 2004;101:15410–15415. doi: 10.1073/pnas.0404587101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Kamath-Loeb AS, Lan L, Nakajima S, Yasui A, Loeb LA. The werner syndrome protein interacts functionally with translesion DNA polymerases. Proc Natl Acad Sci USA. 2007 doi: 10.1073/pnas.0702513104. in press. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Kassam SN, Rainbow AJ. Deficient base excision repair of oxidative damage induced bymethylene blue plus visible light in xeroderma pigmentosum group C fibroblasts. Biochem Biophys Res Commun. 2007;359:1004–1009. doi: 10.1016/j.bbrc.2007.06.005. [DOI] [PubMed] [Google Scholar]
  44. Kathe SD, Shen GP, Wallace SS. Single-stranded breaks in DNA but not oxidative DNA base damages block transcriptional elongation by RNA polymerase II in HeLa cell nuclear extracts. J Biol Chem. 2004;279:18511–18520. doi: 10.1074/jbc.M313598200. [DOI] [PubMed] [Google Scholar]
  45. Khan SG, Levy HL, Legerski R, Quackenbush E, Reardon JT, Emmert S, Sancar A, Li L, Schneider TD, Cleaver JE, Kraemer KH. Xeroderma pigmentosum group C splice mutation associated with autism and hypoglycinemia. Journal of Investigative Dermatology. 1998;111:791–796. doi: 10.1046/j.1523-1747.1998.00391.x. [DOI] [PubMed] [Google Scholar]
  46. Kohji T, Hayashi M, Shioda K, Minagawa M, Morimatsu Y, Tamagawa K, Oda M. Cerebellar neurodegeneration in human hereditary DNA repair disorders. Neurosci Lett. 1998;243:133–138. doi: 10.1016/s0304-3940(98)00109-8. [DOI] [PubMed] [Google Scholar]
  47. Kruman I. Why do neurons enter the cellcycle? Cell Cycle. 2004;3:769–773. [PubMed] [Google Scholar]
  48. Kuraoka I, Bender C, Romieu A, Cadet J, Wood RD, Lindahl T. Removal of oxygen free-radical-induced 5′,8-purine cyclodeoxynucleosides from DNA by the nucleotide excision-repair pathway in human cells. Proceedings of the National Academy of Sciences U S A. 2000;97:3832–3837. doi: 10.1073/pnas.070471597. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Kuraoka I, Robins P, Masutani C, Hanaoka F, Gasparutto D, Cadet J, Wood RD, Lindahl T. Oxygen free radical damage to DNA. Translesion synthesis by human DNA polymerase eta and resistance to exonuclease action at cyclopurine deoxynucleoside residues. Journal of Biological Chemistry. 2001;276:49283–49288. doi: 10.1074/jbc.M107779200. [DOI] [PubMed] [Google Scholar]
  50. Kyng KJ, May A, Brosh RMJ, Cheng WH, Chen C, Becker KG, Bohr VA. The transcriptional response after oxidative stress is defective in Cockayne syndrome group B cells. Oncogene. 2003;22:1135–1149. doi: 10.1038/sj.onc.1206187. [DOI] [PubMed] [Google Scholar]
  51. Lanfear R, Thomas JA, Welch JJ, Brey T, Bromham L. Metabolic rate does not calibrate the molecular clock. Proc Natl Acad Sci U S A. 2007;104:15388–15393. doi: 10.1073/pnas.0703359104. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Laposa RR, Feeney L, Crowley E, Feraudy S, de Cleaver JE. p53 suppression overwhelms DNA polymerase h deficiency in determining the cellular UV DNA damage response. DNA Repair. 2007a doi: 10.1016/j.dnarep.2007.07.005. in press. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Laposa RR, Huang EJ, Cleaver JE. Increased apoptosis, p53 up-regulation, and cerebellar neuronal degeneration in repair-deficient Cockayne syndrome mice. Proc Natl Acad Sci USA. 2007b;104:1389–1394. doi: 10.1073/pnas.0610619104. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Lee KB, Wang D, Lippard SJ, Sharp PA. Transcription-coupled and DNA damage-dependent ubiquitination of RNA polymerase II in vitro. Proc Natl Acad Sci USA. 2002;99:4239–4244. doi: 10.1073/pnas.072068399. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Leech RW, Brumback RA, Miller RH, Otsuka F, Tarone RE, Robbins JH. Cockayne syndrome:clinicopathologic and tissue culture studies of affected siblings. J Neuropathol Exp neurol. 1985;44:507–519. [PubMed] [Google Scholar]
  56. Li H, Vogel H, Holcomb VB, Gu Y, Hasty P. Deletion of Ku70, Ku80, or both causes early aging without substantially increased cancer. Mol Cell Biol. 2007;27:8205–8214. doi: 10.1128/MCB.00785-07. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Lindsey-Boltz LA, Sancar A. RNA poymerase: the most specific damage recognition protein in cellular responses to DNA damage. Proc Nat Acad Sci USA. 2007;104:13213–13214. doi: 10.1073/pnas.0706316104. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Liu K, Akula JD, Falk C, Hansen RM, Fulton AB. The retinal vasculature and function of the neural retina in a rat model of retinopathy of prematurity. Invest Ophthalmol Vis Sci. 2006;47:2639–2647. doi: 10.1167/iovs.06-0016. [DOI] [PubMed] [Google Scholar]
  59. Ljungman M, Zhang F. Blockage of RNA polymerase as a possible trigger for u.v. light-induced apoptosis. Oncogene. 1996;13:823–831. [PubMed] [Google Scholar]
  60. McKinnon PJ, Caldecott KW. DNA strand break repair and human genetic disease. Ann Rev Genomics Human Genetics. 2007;8:37–55. doi: 10.1146/annurev.genom.7.080505.115648. [DOI] [PubMed] [Google Scholar]
  61. McWhir J, Selfridge J, Harrison DJ, Squires S, Melton D. Mice with DNA repair gene (ERCC-1) deficiency have elevated levels of p53, liver nuclear abnormalities and die before weaning. Nature Genetics. 1993;5:217–224. doi: 10.1038/ng1193-217. [DOI] [PubMed] [Google Scholar]
  62. Meydani M, Lipman RD, Han SN, Wu D, Beharka A, Martin KR, Bronson R, Cao G, Smith D, Meydani SN. The effect of long-term dietary supplementation with antioxidants. Ann NY Acad Sci. 1998;854:352–360. doi: 10.1111/j.1749-6632.1998.tb09915.x. [DOI] [PubMed] [Google Scholar]
  63. Nance MA, Berry SA. Cockayne syndrome:review of 140 cases. Amer J Med Genet. 1992;42:68–84. doi: 10.1002/ajmg.1320420115. [DOI] [PubMed] [Google Scholar]
  64. Newman JC, Bailey AD, Weiner AM. Cockayne syndrome group B protein (CSB) plays a general role in chromatin maintenance and remodeling. Proc Nat Acad Sci USA. 2006;103:9613–9618. doi: 10.1073/pnas.0510909103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. Niedernhofer LJ, Garinis GA, Raams A, Lalai AS, Robinson AR, Appeldoorn E, Odijk H, Oostendorp R, Ahmad A, van Leeuwen W, Theil AF, Vermeulen W, van der Horst GT, Meinecke P, Kleijer WJ, Vijg J, Jaspers NG, Hoeijmakers JH. A new progeroid syndrome reveals that genotoxic stress suppresses the somatotroph axis. Nature. 2006;444:1038–1043. doi: 10.1038/nature05456. [DOI] [PubMed] [Google Scholar]
  66. Nouspikel T, Hanawalt P. Terminally differentiated human neurons repair transcribed genes but display attenuated global DNA repair and modulation of repair gene expression. Molecular Cell Biology. 2000;20:1562–1570. doi: 10.1128/mcb.20.5.1562-1570.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  67. Nouspikel T, Hanawalt PC. When parsimony backfires: neglecting DNA repair may doom neurons in Alzheimer’s disease. Bioessays. 2003;25:168–173. doi: 10.1002/bies.10227. [DOI] [PubMed] [Google Scholar]
  68. Nouspikel T, Hanawalt PC. Impaired nucleotide excision repair upon macrophage differentiation is corrected by E1 ubiquitin-activating enzyme. Proc Natl Acad Sci USA. 2006;103:16188–16193. doi: 10.1073/pnas.0607769103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  69. Osterod M, Larsen E, Le Page F, Hengstler JG, Van Der Horst GT, Boiteux S, Klungland A, Epe B. A global DNA repair mechanism involving the Cockayne syndrome B (CSB) gene product can prevent the in vivo accumulation of endogenous oxidative DNA base damage. Oncogene. 2002;21:8232–8239. doi: 10.1038/sj.onc.1206027. [DOI] [PubMed] [Google Scholar]
  70. Otsuka F, Robbins JH. The Cockayne syndrome--an inherited multisystem disorder with cutaneous photosensitivity and defective repair of DNA. Comparison with xeroderma pigmentosum. Am J Dermatopathol. 1985;7:387–392. doi: 10.1097/00000372-198508000-00013. [DOI] [PubMed] [Google Scholar]
  71. Partridge L, Gems D. Benchmarks for ageing studies. Nature. 2007;450:165–167. doi: 10.1038/450165a. [DOI] [PubMed] [Google Scholar]
  72. Proietti De Santis L, Garcia CL, Balajee AS, Latini P, Pichierri P, Nikaido O, Stefanini M, Palitti F. Transcription coupled repair efficiency determines the cell cycle progression and apoptosis after UV exposure in hamster cells. DNA Repair. 2002;1:209–223. doi: 10.1016/s1568-7864(01)00017-9. [DOI] [PubMed] [Google Scholar]
  73. Reichenbach J, Schubert R, Schindler D, Muller K, Bohles H, Zeilen S. Elevated oxidative stress in patients with ataxia telangiectasia. Antioxidants and redox signaling. 2002;4:465–469. doi: 10.1089/15230860260196254. [DOI] [PubMed] [Google Scholar]
  74. Rossi DJ, Bryder D, Seita J, Nussenzweig A, Hoeijmakers J, Weissman IL. Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age. Nature. 2007a;447:725–729. doi: 10.1038/nature05862. [DOI] [PubMed] [Google Scholar]
  75. Rossi DJ, Seita J, Czechowicz A, Bhattacharya D, Bryder D, Weissman IL. Hematopoietic stem cell quiescence attenuates DNA damage response and permits DNA damage accumulation during aging. Cell Cycle. 2007b;6:2371–2376. doi: 10.4161/cc.6.19.4759. [DOI] [PubMed] [Google Scholar]
  76. Smolka MB, Albuquerque CP, Chen SH, Zhou H. Proteome identification of in vivo targets of DNA damage checkpoint kinases. Proc Nat Acad Sci USA. 2007;104:10364–10369. doi: 10.1073/pnas.0701622104. [DOI] [PMC free article] [PubMed] [Google Scholar]
  77. Sun XZ, Harada YN, Takahashi S, Shiomi N, Shiomi T. Purkinje cell degeneration in mice lacking the xeroderma pigmentosum group G gene. J Neurosci Res. 2001;64:348–354. doi: 10.1002/jnr.1085. [DOI] [PubMed] [Google Scholar]
  78. Tanaka K, Kamiuchi S, Ren Y, Yonemasu R, Ichikawa M, Murai H, Yoshino M, Takeuchi S, Saijo M, Nakatsu Y, Miyauchi-Hashimoto H, Horio T. UV-induced skin carcinogenesis in xeroderma pigmentosum group A (XPA) gene-knockout mice with nucleotide excision repair-deficiency. Mutation Research. 2001;477:31–40. doi: 10.1016/s0027-5107(01)00093-8. [DOI] [PubMed] [Google Scholar]
  79. Thorpe GW, Fong CS, Alic N, Higgins VJ, Dawes IW. Cells have distinct mechanisms to maintain protection against different reactive oxygen species: oxidative-stress-response genes. Proc Nat Acad Sci USA. 2004;101:6564–6569. doi: 10.1073/pnas.0305888101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  80. Tsatmali M, Walcott EC, Crossin KL. Newborn neurons acquire high levels of reactive oxygen species and increased mitochondrial proteins upon differentiation from progenitors. Brain research. 2005;1040:137–150. doi: 10.1016/j.brainres.2005.01.087. [DOI] [PubMed] [Google Scholar]
  81. Tuo J, Jaruga P, Rodriguez H, Bohr VA, Dizdaroglu M. Primary fibroblasts of Cockayne syndrome patients are defective in cellular repair of 8-hydroxyguanine and 8-hydroxyadenine resulting from oxidative stress. FASEB. 2003;17:668–674. doi: 10.1096/fj.02-0851com. [DOI] [PubMed] [Google Scholar]
  82. van der Horst GT, Meira L, Gorgels TG, de Wit J, Velasco-Miguel S, Richardson JA, Kamp Y, Vreeswijk MP, Smit B, Bootsma D, Hoeijmakers JH, Friedberg EC. UVB radiation-induced cancer predisposition in Cockayne syndrome group A (Csa) mutant mice. DNA Repair. 2002;1:143–157. doi: 10.1016/s1568-7864(01)00010-6. [DOI] [PubMed] [Google Scholar]
  83. van der Horst GT, van Steeg H, Berg RJ, van Gool AJ, de Wit J, Weeda G, Morreau H, Beems RB, van Kreijl CF, de Gruijl FR, Bootsma D, Hoeijmakers JH. Defective transcription-coupled repair in Cockayne syndrome B mice is associated with skin cancer predisposition. Cell. 1997;89:425–435. doi: 10.1016/s0092-8674(00)80223-8. [DOI] [PubMed] [Google Scholar]
  84. van der Pluijm I, Garinis GA, Brandt RM, Gorgels TG, Wijnhoven SW, Diderich KE, de Wit J, Mitchell JR, van Oostrom C, Beems R, Niedernhofer LJ, Velasco S, Friedberg EC, Tanaka K, van Steeg H, Hoeijmakers JH, van der Horst GT. Impaired genome maintenance suppresses the growth hormone--insulin-like growth factor 1 axis in mice with Cockayne syndrome. PLoS Biology. 2006;5:e2. doi: 10.1371/journal.pbio.0050002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  85. Wallace DC. A mitochondrial paradigm of metabolic and degenerative diseases, aging and cancer:a dawn for evolutionary medicine. Ann Rev Genetics. 2005;39:359–407. doi: 10.1146/annurev.genet.39.110304.095751. [DOI] [PMC free article] [PubMed] [Google Scholar]
  86. Weinstock MA, Stampfer MJ, Lew RA, Willett WC, Sober AJ. Case-control study of melanoma and dietary vitamin D: implications for advocacy of sun protection and sunscreen use. J Invest Dermatol. 1992;98:809–811. doi: 10.1111/1523-1747.ep12499962. [DOI] [PubMed] [Google Scholar]
  87. Yarosh D, Klein J, O’Connor A, Hawk J, Rafal E, Wolf P. Effect of topically applied T4 endonuclease V in liposomes on skin cancer in xeroderma pigmentosum: a randomised study. Xeroderma Pigmentosum Study Group. Lancet. 2001;357:926–929. doi: 10.1016/s0140-6736(00)04214-8. [DOI] [PubMed] [Google Scholar]

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