Mutation Accumulation In Vivo and the Importance of Genome Stability in Aging and Cancer
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Somatic mutations are generally considered as the major cause of cancer. This can be derived from various observations, including the actual presence of mutations in the tumor genome in genes thought to be critically involved in tumor initiation and/or progression, such as TP53,KRAS, and RB1 (Lengauer et al. 1998). Both exogenous (Greenblatt et al. 1994) and endogenous (Jackson et al. 1998) mutagenic mechanisms have been implicated in the induction of these mutations. Modeling of such gene defects into the mouse genome often results in accelerated tumorigenesis (Vijg and van Steeg 1998), confirming the critical role of specific mutations as a cause of cancer. Other indirect evidence involves the general observation that most, if not all, mutagens are also carcinogens and that heritable mutations in genes controlling genome stability pathways often confer a high cancer susceptibility (Vijg and van Steeg 1998).
KeywordsSomatic Mutation Nucleotide Excision Repair Genome Stability Xeroderma Pigmentosum Mutation Accumulation
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- Bootsma D, Kraemer KH, Cleaver J, Hoeijmakers JHJ (1998) Nucleotide excision repair syndromes: xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy. In: Vogelstein B, Kinzler KW (eds) Genetic basis of human cancer, Chapt 13. McGraw-Hill, New York, pp 245–274Google Scholar
- Burnet FM (1974) Intrinsic mutagenesis: a genetic approach to aging. Wiley, New York Campisi J (1996) Replicative senescence: an old lives’ tale? Cell 84: 497–500Google Scholar
- Cleaver JE, Kraemer KH (1995) In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic and molecular bases of inherited disease. 7th edn., vol III. McGraw-Hill New York, pp 43934419Google Scholar
- De Vries A, Van Oostrom CThM, Hofhuis FMA, Dortant PM, Berg RJW, de Gruijl FR, Wester PW, Van Kreijl CF, Capel PJA, Van Steeg H, Verbeek SJ (1995) Increased susceptibility to ultraviolet-B and carcinogens of mice lacking the DNA excision repair gene XPA. Nature 377: 169–173Google Scholar
- De Vries A, Van Oostrom CThM, Dortant PM, Beems RB, Van Kreijl CF, Capel PJA, Van Steeg H (1997) Spontaneous liver tumours and benzo[a)pyrene-induced lymphomas in XPAdeficient mice. Mol Carcinogen 19: 46–53Google Scholar
- Friedberg EC, Walker GC, Siede W (1995) DNA repair and mutagenesis. ASM Press, Washington DCGoogle Scholar
- Greenblatt MS, Bennett WP, Hollstein M, Harris CC (1994) Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Res 54: 48554878Google Scholar
- Levine AJ (1997) p53, the cellular gatekeeper for growth and division. Cell 88:323–331Google Scholar
- Lowe SW, Schmitt SW, Smith SW, Osborne BA, Jacks T (1993) p53 is required for radiation-induced apoptosis in mouse thymocytes. Nature 362: 847–849Google Scholar
- Sugasawa K, Ng JM, Masutani C, Iwai S, van der Spek PJ, Eker AP, Hanaoka F, Bootsma D, Hoeijmakers JH (1998) Xeroderma pigmentosum group C protein complex is the initiator of global genome nucleotide excision repair. Mol Cell 2: 223–232Google Scholar
- Van Oostrom CThM, Boeve M, van den Berg J, de Vries A, Dollé MET, Beems RB, van Kreijl CF, Vijg J, van Steeg H (1999) Effect of heterozygous loss of p53 on benzo[a]pyrene-induced mutations and tumors in DNA repair-deficient XPA mice. Environ Mol Mutagen 34: 124–130Google Scholar