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Repair of Chemical Damage in Mammalian Cells

  • R. B. Setlow

Abstract

The repair of chemical damage to DNA differs in many ways from the repair of radiation damage and its interpretation is often more complicated. For example, most chemicals of environmental concern do not react directly with cellular macromolecules but must first be activated to nucleophiles [1]. Hence the dosimetry of chemicals is complicated and may vary markedly from tissue to tissue, organelle to organelle [2] or from linker to the core region of DNA [3]. The different reactivities between agents reacting directly and those that react indirectly may give rise to products whose yields as a function of dose are completely different even though the products themselves may be the same. Thus Fig. 1 [4] shows a way of estimating chemical doses in vivo from alkylating agents in terms of the level of specific alkylation of hemoglobin. The direct acting agent methylmethanesulfonate (MMS) yields a linear response curve but alkylation from dimethylnitrosamine.(DMN), which needs activation, shows a much lower response and the response increases as some higher power of injected dose measured in mg/kg body weight. On the other hand the development of immunological probes for specific DNA damages offers the possibility of measuring such damages at levels of fmoles [5, 6].

Keywords

Repair Pathway Base Excision Repair Ataxia Telangiectasia Xeroderma Pigmentosum Ataxia Telangiectasia 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    E. C. Miller, Some Current perspectives on chemical carcino-genesis in humans and experimental animals, Cancer Res., 38: 1479 (1978).Google Scholar
  2. 2.
    J. M. Backer and I. B. Weinstein, Mitochondrial DNA is a major target for a dihydrodiol-epoxide derivative of benzo[a]pyrene, Science, 209: 297 (1980).PubMedCrossRefGoogle Scholar
  3. 3.
    C. J. Jahn and G. W. Litman, Accessibility of deoxyribonucleic acid in chromatin to the covalent binding of the chemical carcinogen benzo[a]pyrene, Biochemistry, 18: 1442 (1972).CrossRefGoogle Scholar
  4. 4.
    E. Bailey, T. A. Connors, P. B. Fermer, S. M. Gorf, and J. Rickard, Methylation of cysteine in hemoglobin following exposure to methylating agents, Cancer Res., 41: 2514 (1981).PubMedGoogle Scholar
  5. 5.
    R. Mueller and M. F. Rajewsky, Sensitive radioimmunassay for the detection of 06-ethyldeoxyguanosine in DNA exposed to the carcinogen ethylnitrosourea in vivo or in vitro Zeit f. Naturforsch., 33C: 897 (1978).Google Scholar
  6. 6.
    I. C. Hsu, M. C. Poirier,S. H. Yuspa, D. Grunberger, I. B. Weinstein, R. H. Yolken, and C. C. Harris, Cancer Res., 41: 1091 (1981).Google Scholar
  7. 7.
    R. B. Setlow, DNA damage and carcinogenesis, in: “Chromosome Damage and DNA Repair,” E. Seeberg and K. Kleppe, eds., Plenum Press, New York (1981).Google Scholar
  8. 8.
    R. B. Setlow, Repair deficient human disorders and cancer, Nature, 271: 713 (1978).PubMedCrossRefGoogle Scholar
  9. 9.
    L. C. Erickson, M. 0. Bradley, and K. W. Kohn, M.asurements of DNA damage in Chinese hamster cells treated with equitoxic and equimutagenic doses of nitrosoureas, Cancer Res., 38: 3379 (1978).Google Scholar
  10. 10.
    J. J. Roberts, The repair of DNA modified by cytotoxic muta-genic, and carcinogenic chemicals, Adv. Radiat. Biol., 7: 211 (1978).Google Scholar
  11. 11.
    P. C. Hanawalt, E. C. Friedberg, and C. F. Fox, “DNA Repair Mechanisms,” Academic Press, New York (1978).Google Scholar
  12. 12.
    E. C. Friedberg, U. K. Ehmann, and J. I. Williams, Human diseases associated with defective DNA repair, Adv. Radiat. Biol., 8: 85 (1979).Google Scholar
  13. 13.
    R. B. Setlow, Excision repair of bulky lesions in the DNA of mammalian cells, in: “Chromosome Damage and DNA Repair,” E. Seeberg and K. Kleppe, eds., Plenum Press, New York (1981).Google Scholar
  14. 14.
    L. H. Thompson, D. B. Busch, K. Brookman, C. L. Mooney, and D. A. Glaser, Genetic diversity of UV-sensitive DNA repair mutants of Chinese hamster ovary cells, Proc. Natl. Acad. Sci. USA, 78: 3734 (1981).PubMedCrossRefGoogle Scholar
  15. 15.
    J. D. Regan and R. B. Setlow, Two forms of repair in the DNA of human cells damaged by chemical carcinogens and mutagens, Cancer Res., 34: 3318 (1974).PubMedGoogle Scholar
  16. 16.
    J. D. Regan, A. A. Francis, W. C. Dunn, 0. Hernandez, and D. M. Jerina, Repair of DNA damaged by mutagenic metabolites’of benzo[a]pyrene in human cells, Chem. Biol. Interact., 20: 279 (1978).PubMedCrossRefGoogle Scholar
  17. 17.
    L. L. Yang, V. M. Maher, and J. J. McCormick, Error-free excision of the cytotoxic, mutagenic N2-deoxyguanosine DNA adduct formed in human fibroblasts by (±)-7ß,8a-dihydroxy-9a,10aepoxy-7,8,9,10-tetrahydro-benzo[a]pyrene, Proc. Natl. Acad. Sci. USA, 77: 5933 (1980).PubMedCrossRefGoogle Scholar
  18. 18.
    F. E. Ahmed and R. B. Setlow, DNA repair in xeroderma pigmentosum cells treated with combinations of ultraviolet radiation and N-acetoxy-2-acetylaminofluorene, Cancer Res., 39: 471 (1979).PubMedGoogle Scholar
  19. 19.
    A. J. Brown, T. H. Fickel, J. E. Cleaver, P. H. M. Lohman, M. H. Wade, and R. Waters, Overlapping pathways for repair carcinogens in human fibroblasts, Cancer Res., 39: 2522 (1979).PubMedGoogle Scholar
  20. 20.
    R. B. Setlow, DNA repair pathways, in: “DNA Repair and Muta-genesis in Eukaryotes,” W. M. Generoso, M. D. Shelby, and F. J. de Serres, eds., Plenum Press, New York (1980).Google Scholar
  21. 21.
    J. R. Mehta, D. B. Ludlum, A. Renard, and W. G. Verly, Repair of 06-ethylguaníne in DNA by a chromatin fraction from rat liver: Transfer of the ethyl group to the acceptor protein, Proc. Natl. Acad. Sci. USA, in press (1981).Google Scholar
  22. 22.
    M. Olsson and T. Lindahl, Repair of alkylated DNA in Escherichia coli: Methyl group transfer from 06-methylguanine to a protein cysteine residue, J. Biol. Chem., 255: 10569 (1980).PubMedGoogle Scholar
  23. 23.
    T. Lindahl, DNA glycosylases, endonucleases for apurinic/apyrimidinic sites, and base excision repair, Prog. Nuc1. Acid. Res. Mol. Biol., 22: 135 (1979).Google Scholar
  24. 24.
    B. Singer, N-nitrosoalkylating agents: Formation and persistence of alkyl derivatives in mammalian nucleic acids as contributing factors in carcinogenesis, J. Natl. Cancer Inst., 62: 1329 (1979).PubMedGoogle Scholar
  25. 25.
    D. A. Scudiero, Decreased repair synthesis and defective colony-forming ability of ataxia telangiectasia fibroblast cell strains treated with N-methyl-N’-nitro-N-guanidine, Cancer Res., 40: 984 (1980).PubMedGoogle Scholar
  26. 26.
    A. M. R. Taylor, C. M. Rosney, and J. B. Campbell, Unusual sensitivity of ataxia-telangiectasia cells to bleomycin, Cancer Res., 39: 1046 (1979).Google Scholar
  27. 27.
    P. Cramer and R. B. Painter, Bleomycin-resistant DNA synthesis in ataxia telangiectasia cells, Nature, 291: 671 (1981).PubMedCrossRefGoogle Scholar
  28. 28.
    R. Montesano, H. Bresil, G. Planche-Martel, G. P. Margison, and A. E. Pegg, Effect of chronic treatment of rats with dimethylnitrosamine on the removal of 06-methylguanine from DNA, Cancer Res., 40: 452 (1980).PubMedGoogle Scholar
  29. 29.
    R. S. Day III, C. H. J. Ziolkowski, D. A. Scudiero, S. A. Meyers, M. R. Mattern, Human tumor cell strains defective in the repair of alkylation damage, Carcinogenesis, 1: 21 (1980).PubMedCrossRefGoogle Scholar
  30. 30.
    R. S. Day III, C. H. J. Ziolkowski, D. A. Scudiero, S. A. Meyer, A. S. Lubiniecki, A. J. Girardi, S. M. Galloway, and G. D. Bynum, Defective repair of alkylated DNA by human tumor and SV40-transformed human cell strains, Nature, 288: 724 (1980).PubMedCrossRefGoogle Scholar
  31. 31.
    R. Sklar and B. Strauss, Removal of 06-methylguanine from DNA of normal and xeroderma pigmentosum-derived lymphoblastoid lines, Nature, 289: 417 (1981).PubMedCrossRefGoogle Scholar
  32. 32.
    R. Goth-Goldstein, Repair of DNA damaged by alkylating carcinogens is defective in xeroderma pigmentosum-derived fibroblasts, Nature, 267: 81 (1977).PubMedCrossRefGoogle Scholar
  33. 33.
    A. S. C. Medcalf and P. D. Lawley, Time course of 06-methyl-guanine removal from DNA of N-methyl-N-nitrosourea-treated human fibroblasts, Nature, 289: 796 (1981).PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1983

Authors and Affiliations

  • R. B. Setlow
    • 1
  1. 1.Biology DepartmentBrookhaven National LaboratoryUptonUSA

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