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Nucleotide Excision Repair and its Connection with Cancer and Ageing

  • Chapter
Genome Instability in Cancer Development

Part of the book series: Adances in Experimental Medicine and Biology ((AEMB,volume 570))

Final Conclusions

The intricacies of the GG-NER, TC-NER and presumably the broader TCR reaction combined with the occurrence of functions beyond repair of several of the NER factors and global genome repair defects translates into a complex and highly pleiotropic set of syndromes. However, by careful analysis of patients and mouse mutants we can come to the following simplifications. A defect in the global genome subpathway of NER, as observed in XPC patients, causes the cutaneous features of XP with the high incidence of skin cancer in the UV-exposed parts of the skin. When, in addition, the TC-NER pathway is affected, as in the case of XPA, the additional feature of accelerated neurodegeneration may be occurring as seen to an extreme extent in the DeSanctis-Cacchione form of XP. The CS features, including those apparent in TTD, may be the consequence of a defect in the broader TCR system, with TTD having on top of this the TFIIH instability leading to the typical brittle (unfinished) hair, nails and skin. This discloses some of the mechanistic intricacies that still need to be resolved. The problems caused by defective TCR can be further aggravated by a combination with a deficiency of the GG-NER subpathway, presumably because this increases the overall damage load. This may explain the very severe phenotype exhibited by some XPCS patients. Altogether this highlights the importance of the process that keeps our transcription going despite the continuous induction of DNA lesions: transcription-coupled repair.

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References

  • Aboussekhra, A., M. Biggerstaff, M.K.K. Shivji, J.A. Vilpo, V. Moncollin, V.N. Podust, M. Protic, U. Hubscher, J.-M. Egly, and R.D. Wood. 1995. Mammalian DNA nucleotide excision repair reconstituted with purified components. Cell. 80:859–868.

    Article  CAS  PubMed  Google Scholar 

  • Adimoolam, S., and J.M. Ford. 2002. p53 and DNA damage-inducible expression of the xeroderma pigmentosum group C gene. Proc Natl Acad Sci U S A. 99:12985–90.

    Article  CAS  PubMed  Google Scholar 

  • Adimoolam, S., and J.M. Ford. 2003. p53 and regulation of DNA damage recognition during nucleotide excision repair. DNA Repair (Amst). 2:947–54.

    CAS  Google Scholar 

  • Amundson, S.A., A. Patterson, K.T. Do, and A.J. Fornace, Jr. 2002. A nucleotide excision repair master-switch: p53 regulated coordinate induction of global genomic repair genes. Cancer Biol Ther. 1:145–9.

    CAS  PubMed  Google Scholar 

  • Araujo, S.J., F. Tirode, F. Coin, H. Pospiech, J.E. Syvaoja, M. Stucki, U. Hubscher, J.M. Egly, and R.D. Wood. 2000. Nucleotide excision repair of DNA with recombinant human proteins: definition of the minimal set of factors, active forms of TFIIH, and modulation by CAK. Genes Dev. 14:349–59.

    CAS  PubMed  Google Scholar 

  • Azcoitia, I., L.L. DonCarlos, and L.M. Garcia-Segura. 2003. Are gonadal steroid hormones involved in disorders of brain aging? Aging Cell. 2:31–7.

    Article  CAS  PubMed  Google Scholar 

  • Balaban, R.S., S. Nemoto, and T. Finkel. 2005. Mitochondria, oxidants, and aging. Cell. 120:483–95.

    Article  CAS  PubMed  Google Scholar 

  • Barnes, D.E., A.E. Tomkinson, A.R. Lehmann, A.D.B. Webster, and T. Lindahl. 1992. Mutations in the DNA ligase I gene of an individual with immunodeficienies and cellular hypersensitivity to DNA-damaging agents. Cell. 69:495–503.

    Article  CAS  PubMed  Google Scholar 

  • Berg, R.J., A. de Vries, H. van Steeg, and F.R. de Gruijl. 1997. Relative susceptibilities of XPA knockout mice and their heterozygous and wild-type littermates to UVB-induced skin cancer. Cancer Res. 57:581–4.

    CAS  PubMed  Google Scholar 

  • Bergmann, E., and J.M. Egly. 2001. Trichothiodystrophy, a transcription syndrome. Trends Genet. 17:279–86.

    Article  CAS  PubMed  Google Scholar 

  • Betarbet, R., T.B. Sherer, and J.T. Greenamyre. 2002. Animal models of Parkinson’s disease. Bioessays. 24:308–18.

    Article  CAS  PubMed  Google Scholar 

  • Bodak, N., S. Queille, M.F. Avril, B. Bouadjar, C. Drougard, A. Sarasin, and L. Daya-Grosjean. 1999. High levels of patched gene mutations in basal-cell carcinomas from patients with xeroderma pigmentosum. Proc Natl Acad Sci U S A. 96:5117–22.

    Article  CAS  PubMed  Google Scholar 

  • Bohr, V.A., C.A. Smith, D.S. Okumoto, and P.C. Hanawalt. 1985. DNA repair in an active gene: removal of pyrimidine dimers from the DHFR gene of CHO cells is much more efficient than in the genome overall. Cell. 40:359–369.

    Article  CAS  PubMed  Google Scholar 

  • Boonstra, A., A. van Oudenaren, M. Baert, H. van Steeg, P.J. Leenen, G.T. van der Horst, J.H. Hoeijmakers, H.F. Savelkoul, and J. Garssen. 2001. Differential ultraviolet-B-induced immunomodulation in XPA, XPC, and CSB DNA repair-deficient mice. J Invest Dermatol. 117:141–6.

    Article  CAS  PubMed  Google Scholar 

  • Bootsma, D., and J.H.J. Hoeijmakers. 1993. Engagement with transcription. Nature. 363:114–115.

    Article  CAS  PubMed  Google Scholar 

  • Bootsma, D., K.H. Kraemer, J.E. Cleaver, and J.H. Hoeijmakers. 2002. Nucleotide Excision Repair Syndromes: Xeroderma Pigmentosum, Cockayne Syndrome, and Trichothiodystrophy. In The Genetic Basis of Human Cancer. B. Vogelstein and K.W. Kinzler, editors. McGraw-Hill Medical Publishing Devision. 211–237.

    Google Scholar 

  • Botta, E., T. Nardo, A.R. Lehmann, J.M. Egly, A.M. Pedrini, and M. Stefanini. 2002. Reduced level of the repair/transcription factor TFIIH in trichothiodystrophy. Hum Mol Genet. 11:2919–28.

    Article  CAS  PubMed  Google Scholar 

  • Bradsher, J., J. Auriol, L. Proietti de Santis, S. Iben, J.L. Vonesch, I. Grummt, and J.M. Egly. 2002. CSB is a component of RNA pol I transcription. Mol Cell. 10:819–29.

    Article  CAS  PubMed  Google Scholar 

  • Brash, D.E., N.M. Wikonkal, E. Remenyik, G.T. van der Horst, E.C. Friedberg, D.L. Cheo, H. van Steeg, A. Westerman, and H.J. van Kranen. 2001. The DNA damage signal for Mdm2 regulation, Trp53 induction, and sunburn cell formation in vivo originates from actively transcribed genes. J Invest Dermatol. 117:1234–40.

    Article  CAS  PubMed  Google Scholar 

  • Brooks, P.J. 2002. DNA repair in neural cells: basic science and clinical implications. Mutat Res. 509:93–108.

    CAS  PubMed  Google Scholar 

  • Broughton, B.C., M. Berneburg, H. Fawcett, E.M. Taylor, C.F. Arlett, T. Nardo, M. Stefanini, E. Menefee, V.H. Price, S. Queille, A. Sarasin, E. Bohnert, J. Krutmann, R. Davidson, K.H. Kraemer, and A.R. Lehmann. 2001. Two individuals with features of both xeroderma pigmentosum and trichothiodystrophy highlight the complexity of the clinical outcomes of mutations in the XPD gene. Hum Mol Genet. 10:2539–47.

    Article  CAS  PubMed  Google Scholar 

  • Budd, M.E., and J.L. Campbell. 1995. DNA polymerases required for repair of UV-induced damage in Saccharomyces cerevisiae. Molecular and Cellular Biology. 15:2173–2179.

    CAS  PubMed  Google Scholar 

  • Butterfield, D.A., J. Drake, C. Pocernich, and A. Castegna. 2001. Evidence of oxidative damage in Alzheimer’s disease brain: central role for amyloid beta-peptide. Trends Mol Med. 7:548–54.

    Article  CAS  PubMed  Google Scholar 

  • Campisi, J. 2005. Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors. Cell. 120:513–22.

    Article  CAS  PubMed  Google Scholar 

  • Citterio, E., V. Van Den Boom, G. Schnitzler, R. Kanaar, E. Bonte, R.E. Kingston, J.H. Hoeijmakers, and W. Vermeulen. 2000a. ATP-dependent chromatin remodeling by the Cockayne syndrome B DNA repair-transcription-coupling factor. Mol Cell Biol. 20:7643–53.

    Article  CAS  PubMed  Google Scholar 

  • Citterio, E., W. Vermeulen, and J.H. Hoeijmakers. 2000b. Transcriptional healing. Cell. 101:447–50.

    Article  CAS  PubMed  Google Scholar 

  • Cleaver, J.E., L.H. Thompson, A.S. Richardson, and J.C. States. 1999. A summary of mutations in the UV-sensitive disorders: xeroderma pigmentosum, Cockayne syndrome, and trichothiodystrophy. Hum Mutat. 14:9–22.

    Article  CAS  PubMed  Google Scholar 

  • Coin, F., J. Auriol, A. Tapias, P. Clivio, W. Vermeulen, and J.M. Egly. 2004. Phosphorylation of XPB helicase regulates TFIIH nucleotide excision repair activity. EMBO J. 23:4835–46.

    Article  CAS  PubMed  Google Scholar 

  • Colella, S., T. Nardo, E. Botta, A.R. Lehmann, and M. Stefanini. 2000. Identical mutations in the CSB gene associated with either Cockayne syndrome or the DeSanctis-cacchione variant of xeroderma pigmentosum. Hum Mol Genet. 9:1171–5.

    Article  CAS  PubMed  Google Scholar 

  • Conforti, G., T. Nardo, M. D’Incalci, and M. Stefanini. 2000. Proneness to UV-induced apoptosis in human fibroblasts defective in transcription coupled repair is associated with the lack of Mdm2 transactivation. Oncogene. 19:2714–20.

    Article  CAS  PubMed  Google Scholar 

  • Cooper, P.K., T. Nouspikel, S.G. Clarkson, and S.A. Leadon. 1997. Defective transcriptioncoupled repair of oxidative base damage in Cockayne syndrome patients from XP group G. Science. 275:990–993.

    CAS  PubMed  Google Scholar 

  • Daya-Grosjean, L., C. Robert, C. Drougard, H. Suarez, and A. Sarasin. 1993. High mutation frequency in ras genes of skin tumors isolated from DNA repair deficient xeroderma pigmentosum patients. Cancer Res. 53:1625–9.

    CAS  PubMed  Google Scholar 

  • de Boer, J., J.O. Andressoo, J. de Wit, J. Huijmans, R.B. Beems, H. van Steeg, G. Weeda, G.T. van der Horst, W. van Leeuwen, A.P. Themmen, M. Meradji, and J.H. Hoeijmakers. 2002. Premature aging in mice deficient in DNA repair and transcription. Science. 296:1276–9.

    PubMed  Google Scholar 

  • de Boer, J., J. de Wit, H. van Steeg, R.J.W. Berg, M. Morreau, P. Visser, A.R. Lehmann, M. Duran, J.H.J. Hoeijmakers, and G. Weeda. 1998. A mouse model for the basal transcription/DNA repair syndrome trichothiodystrophy. Mol. Cell. 1:981–990.

    PubMed  Google Scholar 

  • de Laat, W.L., E. Appeldoorn, K. Sugasawa, E. Weterings, N.G. Jaspers, and J.H. Hoeijmakers. 1998. DNA-binding polarity of human replication protein A positions nucleases in nucleotide excision repair. Genes Dev. 12:2598–609.

    PubMed  Google Scholar 

  • de Laat, W.L., N.G.J. Jaspers, and J.H.J. Hoeijmakers. 1999. Molecular mechanism of nucleotide excision repair. Genes Dev. 13:768–785.

    PubMed  Google Scholar 

  • de Vries, A., C.T.M. van Oostrom, F.M.A. Hofhuis, P.M. Dortant, R.J.W. Berg, F.R. de Gruijl, P.W. Wester, C.F. van Kreijl, P.J.A. Capel, H. van Steeg, and S.J. Verbeek. 1995. Increased susceptibility to ultraviolet-B and carcinogens of mice lacking the DNA excision repair gene XPA. Nature. 377:169–173.

    Article  PubMed  Google Scholar 

  • de Waard, H., J. de Wit, T.G. Gorgels, G. van den Aardweg, J.O. Andressoo, M. Vermeij, H. van Steeg, J.H. Hoeijmakers, and G.T. van der Horst. 2003. Cell type-specific hypersensitivity to oxidative damage in CSB and XPA mice. DNA Repair (Amst). 2:13–25.

    Google Scholar 

  • D’Errico, M., A. Calcagnile, F. Canzona, B. Didona, P. Posteraro, R. Cavalieri, R. Corona, I. Vorechovsky, T. Nardo, M. Stefanini, and E. Dogliotti. 2000. UV mutation signature in tumor suppressor genes involved in skin carcinogenesis in xeroderma pigmentosum patients. Oncogene. 19:463–7.

    CAS  PubMed  Google Scholar 

  • D’Errico, M., M. Teson, A. Calcagnile, T. Nardo, N. De Luca, C. Lazzari, S. Soddu, G. Zambruno, M. Stefanini, and E. Dogliotti. 2005. Differential role of transcription-coupled repair in UVB-induced response of human fibroblasts and keratinocytes. Cancer Res. 65:432–8.

    CAS  PubMed  Google Scholar 

  • Dianov, G.L., T. Thybo, Dianova, II, L.J. Lipinski, and V.A. Bohr. 2000. Single nucleotide patch base excision repair is the major pathway for removal of thymine glycol from DNA in human cell extracts. J Biol Chem. 275:11809–13.

    Article  CAS  PubMed  Google Scholar 

  • Drane, P., E. Compe, P. Catez, P. Chymkowitch, and J.M. Egly. 2004. Selective regulation of vitamin D receptor-responsive genes by TFIIH. Mol Cell. 16:187–97.

    Article  CAS  PubMed  Google Scholar 

  • Drapkin, R., J.T. Reardon, A. Ansari, J.C. Huang, L. Zawel, K. Ahn, A. Sancar, and D. Reinberg. 1994. Dual role of TFIIH in DNA excision repair and in transcription by RNA polymerase II. Nature. 368:769–772.

    Article  CAS  PubMed  Google Scholar 

  • Egly, J.M. 2001. The 14th Datta Lecture. TFIIH: from transcription to clinic. FEBS Lett. 498:124–8.

    Article  CAS  PubMed  Google Scholar 

  • Elder, R.T., X.Q. Song, M. Chen, K.M. Hopkins, H.B. Lieberman, and Y. Zhao. 2002. Involvement of rhp23, a Schizosaccharomyces pombe homolog of the human HHR23A and Saccharomyces cerevisiae RAD23 nucleotide excision repair genes, in cell cycle control and protein ubiquitination. Nucleic Acids Res. 30:581–91.

    Article  CAS  PubMed  Google Scholar 

  • Evans, E., J.G. Moggs, J.R. Hwang, J.M. Egly, and R.D. Wood. 1997a. Mechanism of open complex and dual incision formation by human nucleotide excision repair factors. EMBO J. 16:6559–73.

    CAS  PubMed  Google Scholar 

  • Evans, E., J.G. Moggs, J.R. Hwang, J.-M. Egly, and R.D. Wood. 1997b. Mechanism of open complex and dual incision formation by human nucleotide excision repair factors. EMBO J. 16:6559–6573.

    CAS  PubMed  Google Scholar 

  • Fitch, M.E., S. Nakajima, A. Yasui, and J.M. Ford. 2003. In vivo recruitment of XPC to UVinduced cyclobutane pyrimidine dimers by the DDB2 gene product. J Biol Chem. 278:46906–10.

    CAS  PubMed  Google Scholar 

  • Friedberg, E.C., J.P. Bond, D.K. Burns, D.L. Cheo, M.S. Greenblatt, L.B. Meira, D. Nahari, and A.M. Reis. 2000. Defective nucleotide excision repair in xpc mutant mice and its association with cancer predisposition. Mutat Res. 459:99–108.

    CAS  PubMed  Google Scholar 

  • Friedberg, E.C., G.C. Walker, and W. Siede. 1995. DNA repair and mutagenesis. ASM Press, Washington D.C.

    Google Scholar 

  • Fujiwara, Y., C. Masutani, T. Mizukoshi, J. Kondo, F. Hanaoka, and S. Iwai. 1999. Characterization of DNA recognition by the human UV-damaged DNA-binding protein. J Biol Chem. 274:20027–33.

    Article  CAS  PubMed  Google Scholar 

  • Gao, Y., D.O. Ferguson, W. Xie, J.P. Manis, J. Sekiguchi, K.M. Frank, J. Chaudhuri, J. Horner, R.A. DePinho, and F.W. Alt. 2000. Interplay of p53 and DNA-repair protein XRCC4 in tumorigenesis, genomic stability and development. Nature. 404:897–900.

    Article  CAS  PubMed  Google Scholar 

  • Giglia, G., N. Dumaz, C. Drougard, M.F. Avril, L. Daya-Grosjean, and A. Sarasin. 1998. p53 mutations in skin and internal tumors of xeroderma pigmentosum patients belonging to the complementation group C. Cancer Res. 58:4402–9.

    CAS  PubMed  Google Scholar 

  • Giglia-Mari, G., F. Coin, J.A. Ranish, D. Hoogstraten, A. Theil, N. Wijgers, N.G. Jaspers, A. Raams, M. Argentini, P.J. Van Der Spek, E. Botta, M. Stefanini, J.M. Egly, R. Aebersold, J.H. Hoeijmakers, and W. Vermeulen. 2004. A new, tenth subunit of TFIIH is responsible for the DNA repair syndrome trichothiodystrophy group A. Nat Genet. 36:714–9.

    Article  CAS  PubMed  Google Scholar 

  • Glockzin, S., F.X. Ogi, A. Hengstermann, M. Scheffner, and C. Blattner. 2003. Involvement of the DNA repair protein hHR23 in p53 degradation. Mol Cell Biol. 23:8960–9.

    Article  CAS  PubMed  Google Scholar 

  • Goode, E.L., C.M. Ulrich, and J.D. Potter. 2002. Polymorphisms in DNA repair genes and associations with cancer risk. Cancer Epidemiol Biomarkers Prev. 11:1513–30.

    CAS  PubMed  Google Scholar 

  • Graham, J.M., Jr., K. Anyane-Yeboa, A. Raams, E. Appeldoorn, W.J. Kleijer, V.H. Garritsen, D. Busch, T.G. Edersheim, and N.G. Jaspers. 2001. Cerebro-oculo-facio-skeletal syndrome with a nucleotide excision-repair defect and a mutated XPD gene, with prenatal diagnosis in a triplet pregnancy. Am J Hum Genet. 69:291–300.

    CAS  PubMed  Google Scholar 

  • Groisman, R., J. Polanowska, I. Kuraoka, J. Sawada, M. Saijo, R. Drapkin, A.F. Kisselev, K. Tanaka, and Y. Nakatani. 2003. The ubiquitin ligase activity in the DDB2 and CSA complexes is differentially regulated by the COP9 signalosome in response to DNA damage. Cell. 113:357–67.

    Article  CAS  PubMed  Google Scholar 

  • Gunz, D., M.T. Hess, and H. Naegeli. 1996. Recognition of DNA adducts by human nucleotide excision repair. Evidence for a thermodynamic probing mechanism. J Biol Chem. 271:25089–98.

    CAS  PubMed  Google Scholar 

  • Harada, Y.N., N. Shiomi, M. Koike, M. Ikawa, M. Okabe, S. Hirota, Y. Kitamura, M. Kitagawa, T. Matsunaga, O. Nikaido, and T. Shiomi. 1999. Postnatal growth failure, short life span, and early onset of cellular senescence and subsequent immortalization in mice lacking the xeroderma pigmentosum group G gene. Mol Cell Biol. 19:2366–72.

    CAS  PubMed  Google Scholar 

  • Harper, J.W., and S.J. Elledge. 1998. The role of Cdk7 in CAK function, a retroretrospective. Genes Dev. 12:285–9.

    CAS  PubMed  Google Scholar 

  • Hasty, P., J. Campisi, J. Hoeijmakers, H. van Steeg, and J. Vijg. 2003. Aging and genome maintenance: lessons from the mouse? Science. 299:1355–9.

    Article  CAS  PubMed  Google Scholar 

  • Hayashi, M. 1999. [Apoptotic cell death in child-onset neurodegenerative disorders]. No To Hattatsu. 31:146–52.

    CAS  PubMed  Google Scholar 

  • Hoeijmakers, J.H. 2001. Genome maintenance mechanisms for preventing cancer. Nature. 411:366–74.

    Article  CAS  PubMed  Google Scholar 

  • Hoogstraten, D., A.L. Nigg, H. Heath, L.H. Mullenders, R. van Driel, J.H. Hoeijmakers, W. Vermeulen, and A.B. Houtsmuller. 2002. Rapid switching of TFIIH between RNA polymerase I and II transcription and DNA repair in vivo. Mol Cell. 10:1163–74.

    Article  CAS  PubMed  Google Scholar 

  • Horibata, K., Y. Iwamoto, I. Kuraoka, N.G. Jaspers, A. Kurimasa, M. Oshimura, M. Ichihashi, and K. Tanaka. 2004. Complete absence of Cockayne syndrome group B gene product gives rise to UV-sensitive syndrome but not Cockayne syndrome. Proc Natl Acad Sci U S A. 101:15410–5.

    Article  CAS  PubMed  Google Scholar 

  • Hwang, B.J., and G. Chu. 1993. Purification and characterization of a human protein that binds to damaged DNA. Biochemistry. 32:1657–66.

    Article  CAS  PubMed  Google Scholar 

  • Hwang, B.J., J.M. Ford, P.C. Hanawalt, and G. Chu. 1999. Expression of the p48 xeroderma pigmentosum gene is p53-dependent and is involved in global genomic repair. Proc Natl Acad Sci U S A. 96:424–8.

    CAS  PubMed  Google Scholar 

  • Hwang, B.J., S. Toering, U. Francke, and G. Chu. 1998. p48 Activates a UV-damaged-DNA binding factor and is defective in xeroderma pigmentosum group E cells that lack binding activity. Mol Cell Biol. 18:4391–9.

    CAS  PubMed  Google Scholar 

  • Iben, S., H. Tschochner, M. Bier, D. Hoogstraten, P. Hozak, J.M. Egly, and I. Grummt. 2002. TFIIH plays an essential role in RNA polymerase I transcription. Cell. 109:297–306.

    Article  CAS  PubMed  Google Scholar 

  • Itin, P.H., A. Sarasin, and M.R. Pittelkow. 2001. Trichothiodystrophy: update on the sulfurdeficient brittle hair syndromes. J Am Acad Dermatol. 44:891–920; quiz 921-4.

    Article  CAS  PubMed  Google Scholar 

  • Itoh, M., M. Hayashi, K. Shioda, M. Minagawa, F. Isa, K. Tamagawa, Y. Morimatsu, and M. Oda. 1999. Neurodegeneration in hereditary nucleotide repair disorders. Brain Dev. 21:326–33.

    Article  CAS  PubMed  Google Scholar 

  • Itoh, T., C. O’shea, and S. Linn. 2003. Impaired regulation of tumor suppressor p53 caused by mutations in the xeroderma pigmentosum DDB2 gene: mutual regulatory interactions between p48(DDB2) and p53. Mol Cell Biol. 23:7540–53.

    Article  CAS  PubMed  Google Scholar 

  • James, M., J. Mansbridge, and C. Kidson. 1982. Ultraviolet radiation sensitivity of proliferating and differentiated human neuroblastoma cells. Int J Radiat Biol Relat Stud Phys Chem Med. 41:547–56.

    CAS  PubMed  Google Scholar 

  • Jans, J., W. Schul, Y.G. Sert, Y. Rijksen, H. Rebel, A.P. Eker, S. Nakajima, H. van Steeg, F.R. de Gruijl, A. Yasui, J.H. Hoeijmakers, and G.T. van der Horst. 2005. Powerful skin cancer protection by a CPD-photolyase transgene. Curr Biol. 15:105–15.

    Article  CAS  PubMed  Google Scholar 

  • Jaspers, N.G., A. Raams, M.J. Kelner, J.M. Ng, Y.M. Yamashita, S. Takeda, T.C. McMorris, and J.H. Hoeijmakers. 2002. Anti-tumour compounds illudin S and Irofulven induce DNA lesions ignored by global repair and exclusively processed by transcription-and replication-coupled repair pathways. DNA Repair (Amst). 1:1027–38.

    CAS  Google Scholar 

  • Keriel, A., A. Stary, A. Sarasin, C. Rochette-Egly, and J.M. Egly. 2002. XPD mutations prevent TFIIH-dependent transactivation by nuclear receptors and phosphorylation of RARalpha. Cell. 109:125–35.

    Article  CAS  PubMed  Google Scholar 

  • Kraemer, K.H., M.M. Lee, and J. Scotto. 1987. Xeroderma pigmentosum. Cutaneous, ocular, and neurologic abnormalities in 830 published cases. Arch Dermatol. 123:241–50.

    Article  CAS  PubMed  Google Scholar 

  • Lehmann, A.R. 2001. The xeroderma pigmentosum group D (XPD) gene: one gene, two functions, three diseases. Genes Dev. 15:15–23.

    Article  CAS  PubMed  Google Scholar 

  • Li, L., X. Lu, C.A. Peterson, and R.J. Legerski. 1995. An interaction between the DNA repair factor XPA and replication protein A appears essential for nucleotide excision repair. Mol Cell Biol. 15:5396–402.

    CAS  PubMed  Google Scholar 

  • Lindahl, T. 1993. Instability and decay of the primary structure of DNA. Nature. 362:709–715.

    Article  CAS  PubMed  Google Scholar 

  • Lindenbaum, Y., D. Dickson, P. Rosenbaum, K. Kraemer, I. Robbins, and I. Rapin. 2001. Xeroderma pigmentosum/cockayne syndrome complex: first neuropathological study and review of eight other cases. Eur J Paediatr Neurol. 5:225–42.

    Article  CAS  PubMed  Google Scholar 

  • Liu, J., S. Akoulitchev, A. Weber, H. Ge, S. Chuikov, D. Libutti, X.W. Wang, J.W. Conaway, C.C. Harris, R.C. Conaway, D. Reinberg, and D. Levens. 2001. Defective interplay of activators and repressors with TFIH in xeroderma pigmentosum. Cell. 104:353–63.

    Article  CAS  PubMed  Google Scholar 

  • Ljungman, M., and D.P. Lane. 2004. Transcription-guarding the genome by sensing DNA damage. Nat Rev Cancer. 4:727–37.

    Article  CAS  PubMed  Google Scholar 

  • Ljungman, M., and F. Zhang. 1996. Blockage of RNA polymerase as a possible trigger for u.v. light-induced apoptosis. Oncogene. 13:823–31.

    CAS  PubMed  Google Scholar 

  • Lu, Y., H. Lian, P. Sharma, N. Schreiber-Agus, R.G. Russell, L. Chin, G.T. van der Horst, and D.B. Bregman. 2001. Disruption of the Cockayne syndrome B gene impairs spontaneous tumorigenesis in cancer-predisposed Ink4a/ARF knockout mice. Mol Cell Biol. 21:1810–8.

    CAS  PubMed  Google Scholar 

  • Meira, L.B., J.M. Graham, Jr., C.R. Greenberg, D.B. Busch, A.T. Doughty, D.W. Ziffer, D.M. Coleman, I. Savre-Train, and E.C. Friedberg. 2000. Manitoba aboriginal kindred with original cerebro-oculo-facio-skeletal syndrome has a mutation in the Cockayne syndrome group B (CSB) gene. Am J Hum Genet. 66:1221–8.

    Article  CAS  PubMed  Google Scholar 

  • Mellon, I., V.A. Bohr, C.A. Smith, and P.C. Hanawalt. 1986. Preferential DN A repair of an active gene in human cells. Proc Natl Acad Sci U S A. 83:8878–8882.

    CAS  PubMed  Google Scholar 

  • Mellon, I., G. Spivak, and P.C. Hanawalt. 1987. Selective removal of transcription-blocking DNA damage from the transcribed strand of the mammalian DHFR gene. Cell. 51:241–249.

    Article  CAS  PubMed  Google Scholar 

  • Miyauchi-Hashimoto, H., K. Tanaka, and T. Horio. 1996. Enhanced inflammation and immunosuppression by ultraviolet radiation in xeroderma pigmentosum group A (XPA) model mice. J Invest Dermatol. 107:343–8.

    Article  CAS  PubMed  Google Scholar 

  • Mu, D., D.S. Hsu, and A. Sancar. 1996. Reaction mechanism of human DNA repair excision nuclease. J. Biol. Chem. 271:8285–8294.

    Article  CAS  PubMed  Google Scholar 

  • Nakane, H., S. Takeuchi, S. Yuba, M. Saijo, Y. Nakatsu, T. Ishikawa, S. Hirota, Y. Kitamura, Y. Kato, Y. Tsunoda, H. Miyauchi, T. Horio, T. Tokunaga, T. Matsunaga, O. Nikaido, Y. Nishimune, Y. Okada, and K. Tanaka. 1995. High incedence of ultraviolet-B-or chemicalcarcinogen-induced skin tomours in mice lacking the xeroderma pigmentosum group A gene. Nature. 377:165–168.

    Article  CAS  PubMed  Google Scholar 

  • Nakura, J., L. Ye, A. Morishima, K. Kohara, and T. Miki. 2000. Helicases and aging. Cell Mol Life Sci. 57:716–30.

    CAS  PubMed  Google Scholar 

  • Nance, M.A., and S.A. Berry. 1992. Cockayne syndrome: Review of 140 cases. Am. J. Med. Genet. 42:68–84.

    Article  CAS  PubMed  Google Scholar 

  • Ng, J.M., W. Vermeulen, G.T. van der Horst, S. Bergink, K. Sugasawa, H. Vrieling, and J.H. Hoeijmakers. 2003. A novel regulation mechanism of DNA repair by damage-induced and RAD23-dependent stabilization of xeroderma pigmentosum group C protein. Genes Dev. 17:1630–45.

    Article  CAS  PubMed  Google Scholar 

  • Niedernhofer, L.J., J. Essers, G. Weeda, B. Beverloo, J. de Wit, M. Muijtjens, H. Odijk, J.H. Hoeijmakers, and R. Kanaar. 2001. The structure-specific endonuclease Ercc1-Xpf is required for targeted gene replacement in embryonic stem cells. EMBO J. 20:6540–9.

    Article  CAS  PubMed  Google Scholar 

  • Nouspikel, T., and P.C. Hanawalt. 2000. Terminally differentiated human neurons repair transcribed genes but display attenuated global DNA repair and modulation of repair gene expression. Mol Cell Biol. 20:1562–70.

    Article  CAS  PubMed  Google Scholar 

  • Nouspikel, T., and P.C. Hanawalt. 2002. DNA repair in terminally differentiated cells. DNA Repair (Amst). 1:59–75.

    CAS  Google Scholar 

  • O’Donovan, A., A.A. Davies, J.G. Moggs, S.C. West, and R.D. Wood. 1994. XPG endonuclease makes the 3’ incision in human DNA nucleotide excision repair. Nature. 371:432–435.

    CAS  PubMed  Google Scholar 

  • Parkes, T.L., A.J. Elia, D. Dickinson, A.J. Hilliker, J.P. Phillips, and G.L. Boulianne. 1998. Extension of Drosophila lifespan by overexpression of human SOD1 in motorneurons. Nat Genet. 19:171–4.

    Article  CAS  PubMed  Google Scholar 

  • Payne, A., and G. Chu. 1994. Xeroderma pigmentosum group E binding factor recognizes a broad spectrum of DNA damage. Mutat Res. 310:89–102.

    CAS  PubMed  Google Scholar 

  • Rademakers, S., M. Volker, D. Hoogstraten, A.L. Nigg, M.J. Mone, A.A. Van Zeeland, J.H. Hoeijmakers, A.B. Houtsmuller, and W. Vermeulen. 2003. Xeroderma pigmentosum group A protein loads as a separate factor onto DNA lesions. Mol Cell Biol. 23:5755–67.

    Article  CAS  PubMed  Google Scholar 

  • Randerath, E., G.D. Zhou, and K. Randerath. 1997a. Organ-specific oxidative DNA damage associated with normal birth in rats. Carcinogenesis. 18:859–66.

    CAS  PubMed  Google Scholar 

  • Randerath, K., G.D. Zhou, S.A. Monk, and E. Randerath. 1997b. Enhanced levels in neonatal rat liver of 7,8-dihydro-8-oxo-2’-deoxyguanosine (8-hydroxydeoxyguanosine), a major mutagenic oxidative DNA lesion. Carcinogenesis. 18:1419–21.

    CAS  PubMed  Google Scholar 

  • Randerath, K., G.D. Zhou, R.L. Somers, J.H. Robbins, and P.J. Brooks. 2001. A 32P-postlabeling assay for the oxidative DNA lesion 8,5’-cyclo-2’-deoxyadenosine in mammalian tissues: evidence that four type II I-compounds are dinucleotides containing the lesion in the 3’ nucleotide. J Biol Chem. 276:36051–7.

    Article  CAS  PubMed  Google Scholar 

  • Rapin, I., Y. Lindenbaum, D.W. Dickson, K.H. Kraemer, and J.H. Robbins. 2000. Cockayne syndrome and xeroderma pigmentosum. Neurology. 55:1442–9.

    CAS  PubMed  Google Scholar 

  • Reardon, J.T., A.F. Nichols, S. Keeney, C.A. Smith, J.S. Taylor, S. Linn, and A. Sancar. 1993. Comparative analysis of binding of human damaged DNA-binding protein (XPE) and escherichia-coli damage recognition protein (UvrA) to the major ultraviolet photoproducts-T[CS]TT[Ts]TT[6-4]T and T(Dewar)T. J. Biol. Chem. 268:21301–21308.

    CAS  PubMed  Google Scholar 

  • Riedl, T., F. Hanaoka, and J.M. Egly. 2003. The comings and goings of nucleotide excision repair factors on damaged DNA. EMBO J. 22:5293–303.

    Article  CAS  PubMed  Google Scholar 

  • Sands, A.T., A. Abuin, A. Sanchez, C.J. Conti, and A. Bradley. 1995. High susceptibility to ultraviolet-induced carcinogenesis in mice lacking XPC. Nature. 377:162–165.

    Article  CAS  PubMed  Google Scholar 

  • Schaeffer, L., V. Moncollin, R. Roy, A. Staub, M. Mezzina, A. Sarasin, G. Weeda, J.H.J. Hoeijmakers, and J.M. Egly. 1994. The ERCC2/DNA repair protein is associated with the class II BTF2/TFIIH transcription factor. EMBO J. 13:2388–2392.

    CAS  PubMed  Google Scholar 

  • Schaeffer, L., R. Roy, S. Humbert, V. Moncollin, W. Vermeulen, J.H. Hoeijmakers, P. Chambon, and J.M. Egly. 1993a. DNA repair helicase: a component of BTF2 (TFIIH) basic transcription factor. Science. 260:58–63.

    CAS  PubMed  Google Scholar 

  • Schaeffer, L., R. Roy, S. Humbert, V. Moncollin, W. Vermeulen, J.H.J. Hoeijmakers, P. Chambon, and J. Egly. 1993b. DNA repair helicase: a component of BTF2 (TFIIH) basic transcription factor. Science. 260:58–63.

    CAS  PubMed  Google Scholar 

  • Shiomi, N., S. Kito, M. Oyama, T. Matsunaga, Y.N. Harada, M. Ikawa, M. Okabe, and T. Shiomi. 2004. Identification of the XPG region that causes the onset of Cockayne syndrome by using Xpg mutant mice generated by the cDNA-mediated knock-in method. Mol Cell Biol. 24:3712–9.

    Article  CAS  PubMed  Google Scholar 

  • Shiomi, N., M. Mori, S. Kito, Y.N. Harada, K. Tanaka, and T. Shiomi. 2005. Severe growth retardation and short life span of double-mutant mice lacking Xpa and exon 15 of Xpg. DNA Repair (Amst). 4:351–7.

    CAS  Google Scholar 

  • Shivji, M.K.K., V.N. Podust, U. Hubscher, and R.D. Wood. 1995. Nucleotide excision repair DNA synthesis by DNA polymerase epsilon in the presence of PCNA, RFC, and RPA. Biochemistry. 34:5011–5017.

    Article  CAS  PubMed  Google Scholar 

  • Sibghat-Ullah, I. Husain, W. Carlton, and A. Sancar. 1989. Human nucleotide excision repair in vitro: repair of pyrimidine dimers, psoralen and cisplatin adducts by HeLa cell-free extract. Nucleic Acids Res. 17:4471–84.

    CAS  Google Scholar 

  • Sijbers, A.M., W.L. de Laat, R.R. Ariza, M. Biggerstaff, Y.F. Wei, J.G. Moggs, K.C. Carter, B.K. Shell, E. Evans, M.C. de Jong, S. Rademakers, J. de Rooij, N.G. Jaspers, J.H. Hoeijmakers, and R.D. Wood. 1996. Xeroderma pigmentosum group F caused by a defect in a structure-specific DNA repair endonuclease. Cell. 86:811–822.

    Article  CAS  PubMed  Google Scholar 

  • Spatz, A., G. Giglia-Mari, S. Benhamou, and A. Sarasin. 2001. Association between DNA repair-deficiency and high level of p53 mutations in melanoma of Xeroderma pigmentosum. Cancer Res. 61:2480–6.

    CAS  PubMed  Google Scholar 

  • Stigger, E., R. Drissi, and S.H. Lee. 1998. Functional analysis of human replication protein A in nucleotide excision repair. J Biol Chem. 273:9337–43.

    Article  CAS  PubMed  Google Scholar 

  • Sugasawa, K., J.M. Ng, C. Masutani, S. Iwai, P.J. van der Spek, A.P. Eker, F. Hanaoka, D. Bootsma, and J.H. Hoeijmakers. 1998. Xeroderma pigmentosum group C protein complex is the initiator of global genome nucleotide excision repair. Mol Cell. 2:223–32.

    Article  CAS  PubMed  Google Scholar 

  • Sun, X.Z., Y.N. Harada, S. Takahashi, N. Shiomi, and T. Shiomi. 2001. Purkinje cell degeneration in mice lacking the xeroderma pigmentosum group G gene. J Neurosci Res. 64:348–54.

    Article  CAS  PubMed  Google Scholar 

  • Takada, K., and L.E. Becker. 1986. Cockayne’s syndrome: report of two autopsy cases associated with neurofibrillary tangles. Clin Neuropathol. 5:64–8.

    CAS  PubMed  Google Scholar 

  • Tan, T., and G. Chu. 2002. p53 Binds and activates the xeroderma pigmentosum DDB2 gene in humans but not mice. Mol Cell Biol. 22:3247–54.

    CAS  PubMed  Google Scholar 

  • Tang, J.Y., B.J. Hwang, J.M. Ford, P.C. Hanawalt, and G. Chu. 2000. Xeroderma pigmentosum p48 gene enhances global genomic repair and suppresses UV-induced mutagenesis. Mol Cell. 5:737–44.

    Article  CAS  PubMed  Google Scholar 

  • Tian, M., R. Shinkura, N. Shinkura, and F.W. Alt. 2004. Growth retardation, early death, and DNA repair defects in mice deficient for the nucleotide excision repair enzyme XPF. Mol Cell Biol. 24:1200–5.

    CAS  PubMed  Google Scholar 

  • van den Boom, V., N.G. Jaspers, and W. Vermeulen. 2002. When machines get stuck— obstructed RNA polymerase II: displacement, degradation or suicide. Bioessays. 24:780–4.

    PubMed  Google Scholar 

  • van der Horst, G.T., L. Meira, T.G. Gorgels, J. de Wit, S. Velasco-Miguel, J.A. Richardson, Y. Kamp, M.P. Vreeswijk, B. Smit, D. Bootsma, J.H. Hoeijmakers, and E.C. Friedberg. 2002. UVB radiation-induced cancer predisposition in Cockayne syndrome group A (Csa) mutant mice. DNA Repair (Amst). 1:143–57.

    Google Scholar 

  • van der Horst, G.T., H. van Steeg, R.J. Berg, A.J. van Gool, J. de Wit, G. Weeda, H. Morreau, R.B. Beems, C.F. van Kreijl, F.R. de Gruijl, D. Bootsma, and J.H. Hoeijmakers. 1997a. Defective transcription-coupled repair in Cockayne syndrome B mice is associated with skin cancer predisposition. Cell. 89:425–35.

    PubMed  Google Scholar 

  • van der Horst, G.T.J., H. van Steeg, R.J.W. Berg, A. van Gool, J. de Wit, G. Weeda, H. Morreau, R.B. Beems, C.F. van Kreijl, F.R. de Gruijl, D. Bootsma, and J.H.J. Hoeijmakers. 1997b. Defective transcription-coupled repair in Cockayne syndrome B mice is associated with skin cancer predisposition. Cell. 89:425–35.

    PubMed  Google Scholar 

  • van der Maazen, R.W., B.J. Kleiboer, I. Verhagen, and A.J. van der Kogel. 1993. Repair capacity of adult rat glial progenitor cells determined by an in vitro clonogenic assay after in vitro or in vivo fractionated irradiation. Int J Radiat Biol. 63:661–6.

    PubMed  Google Scholar 

  • Vermeulen, W., S. Rademakers, N.G. Jaspers, E. Appeldoorn, A. Raams, B. Klein, W.J. Kleijer, L.K. Hansen, and J.H. Hoeijmakers. 2001. A temperature-sensitive disorder in basal transcription and DNA repair in humans. Nat Genet. 27:299–303.

    Article  CAS  PubMed  Google Scholar 

  • Vermeulen, W., A.J. van Vuuren, M. Chipoulet, L. Schaeffer, E. Appeldoorn, G. Weeda, N.G.J. Jaspers, A. Priestley, C.F. Arlett, A.R. Lehmann, M. Stefanini, M. Mezzina, A. Sarasin, D. Bootsma, J.-M. Egly, and J.H.J. Hoeijmakers. 1994. Three unusual repair deficiencies associated with transcription factor BTF2(TFIIH): Evidence for the existence of a transcription syndrome. Cold Spring Harb. Symp. Quant. Biol. 59:317–329.

    CAS  PubMed  Google Scholar 

  • Volker, M., M.J. Mone, P. Karmakar, A. van Hoffen, W. Schul, W. Vermeulen, J.H. Hoeijmakers, R. van Driel, A.A. van Zeeland, and L.H. Mullenders. 2001. Sequential assembly of the nucleotide excision repair factors in vivo. Mol Cell. 8:213–24.

    Article  CAS  PubMed  Google Scholar 

  • Wakasugi, M., A. Kawashima, H. Morioka, S. Linn, A. Sancar, T. Mori, O. Nikaido, and T. Matsunaga. 2002. DDB accumulates at DNA damage sites immediately after UV irradiation and directly stimulates nucleotide excision repair. J Biol Chem. 277:1637–40.

    CAS  PubMed  Google Scholar 

  • Wang, G., L. Chuang, X. Zhang, S. Colton, A. Dombkowski, J. Reiners, A. Diakiw, and X.S. Xu. 2004. The initiative role of XPC protein in cisplatin DNA damaging treatmentmediated cell cycle regulation. Nucleic Acids Res. 32:2231–40.

    CAS  PubMed  Google Scholar 

  • Wang, X.W., W. Vermeulen, J.D. Coursen, M. Gibson, S.E. Lupold, K. Forrester, G. Xu, L. Elmore, H. Yeh, J.H. Hoeijmakers, and C.C. Harris. 1996. The XPB and XPD DNA helicases are components of the p53-mediated apoptosis pathway. Genes Dev. 10:1219–32.

    CAS  PubMed  Google Scholar 

  • Weeda, G., I. Donker, J. de Wit, H. Morreau, R. Janssens, C.J. Vissers, A. Nigg, H. van Steeg, D. Bootsma, and J.H.J. Hoeijmakers. 1997. Disruption of mouse ERCC1 results in a novel repair syndrome with growth failure, nuclear abnormalities and senescence. Curr Biol. 7:427–39.

    Article  CAS  PubMed  Google Scholar 

  • Wijnhoven, S.W., H.J. Kool, L.H. Mullenders, A.A. van Zeeland, E.C. Friedberg, G.T. van der Horst, H. van Steeg, and H. Vrieling. 2000. Age-dependent spontaneous mutagenesis in Xpc mice defective in nucleotide excision repair. Oncogene. 19:5034–7.

    Article  CAS  PubMed  Google Scholar 

  • Winkler, G.S., S.J. Araujo, U. Fiedler, W. Vermeulen, F. Coin, J.M. Egly, J.H. Hoeijmakers, R.D. Wood, H.T. Timmers, and G. Weeda. 2000. TFIIH with inactive XPD helicase functions in transcription initiation but is defective in DNA repair. J Biol Chem. 275:4258–66.

    Article  CAS  PubMed  Google Scholar 

  • Winkler, G.S., K. Sugasawa, A.P. Eker, W.L. de Laat, and J.H. Hoeijmakers. 2001. Novel functional interactions between nucleotide excision DNA repair proteins influencing the enzymatic activities of TFIIH, XPG, and ERCC1-XPF. Biochemistry. 40:160–5.

    Article  CAS  PubMed  Google Scholar 

  • Wood, R.D. 1999. DNA damage recognition during nucleotide excision repair in mammalian cells. Biochimie. 81:39–44.

    Article  CAS  PubMed  Google Scholar 

  • Wood, R.D., P. Robins, and T. Lindahl. 1988. Complementation of the xeroderma pigmentosum DNA repair defect in cell-free extracts. Cell. 53:97–106.

    Article  CAS  PubMed  Google Scholar 

  • Yamaizumi, M., and T. Sugano. 1994. U.v.-induced nuclear accumulation of p53 is evoked through DNA damage of actively transcribed genes independent of the cell cycle. Oncogene. 9:2775–84.

    CAS  PubMed  Google Scholar 

  • Yokoi, M., C. Masutani, T. Maekawa, K. Sugasawa, Y. Ohkuma, and F. Hanaoka. 2000. The xeroderma pigmentosum group C protein complex XPC-HR23B plays an important role in the recruitment of transcription factor IIH to damaged DNA. J Biol Chem. 275:9870–5.

    CAS  PubMed  Google Scholar 

  • You, J.S., M. Wang, and S.H. Lee. 2003. Biochemical analysis of the damage recognition process in nucleotide excision repair. J Biol Chem. 278:7476–85.

    CAS  PubMed  Google Scholar 

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  1. MGC Department of Cell Biology and Genetics, Center for Biomedical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands

    Jaan-Olle Andressoo, Jan H.J. Hoeijmakers & Harm de Waard

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  1. Jaan-Olle Andressoo
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Editors and Affiliations

  1. Max-Planck Institute of Biochemistry, Martinsried, Germany

    Erich A. Nigg

  2. State University of New York, Buffalo

    Nathan Back

  3. The Weizmann Institute of Science, Israel

    Irun R. Cohen

  4. Wistar Institute, USA

    David Kritchevsky

  5. N. S. Kline Institute for Psychiatric Research, USA

    Abel Lajtha

  6. University of Milan, Italy

    Rodolfo Paoletti

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Andressoo, JO., Hoeijmakers, J.H., de Waard, H. (2005). Nucleotide Excision Repair and its Connection with Cancer and Ageing. In: Back, N., Cohen, I.R., Kritchevsky, D., Lajtha, A., Paoletti, R., Nigg, E.A. (eds) Genome Instability in Cancer Development. Adances in Experimental Medicine and Biology, vol 570. Springer, Dordrecht. https://doi.org/10.1007/1-4020-3764-3_3

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