Repair of Alkylated DNA by Cell Extracts from Various Organs and Species

  • Anthony E. Pegg
Part of the Basic Life Sciences book series


Simple alkylating agents form an interesting class of chemical carcinogens whose interaction with DNA is relatively well understood (1–7). These carcinogens include agents such as alkyl alkanesulfonates, alkylnitrosamides, alkylnitrosoguanidines, and monoalkyltriazines that are direct acting and the chemically-stable nitrosamines, dialkylhydrazines, and dialkyltriazines that require enzymatic activation to generate the alkylating species. The major adducts formed by these agents on reaction with DNA in target and nontarget tissues have been quantitated and their persistence with time measured (1,2,5,6). These studies have suggested that certain adducts are more likely to be responsible for the initiation of tumors than others; particular emphasis has been placed on the potential role of O 6-alkylguanine. O 6-Alkylguanine is known to miscode in nucleic acid synthesis and to lead to mutations. Furthermore, its rate of removal from DNA. differs from tissue to tissue, and the persistence correlates with sensitivity to tumor initiation (1,2,5). These results underline the significant role that DNA repair may play in preventing a carcinogenesis by alkylating agents. Other alkylated bases may also have the potential to initiate tumors, but the rapid removal would minimize their effect.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Pegg, A.E. 1977. Formation and metabolism of alkylated purines: Possible role in carcinogenesis by N-nitroso compounds and alkylating agents. Adv. Cancer Res. 25: 195–269.PubMedCrossRefGoogle Scholar
  2. 2.
    Margison, G.P., and P.J. O’Connor. 1979. Nucleic acid modification by N-nitroso compounds. In: Chemical Carcinogens and DNA. P.L. Grover, ed. CRC Press: FL. pp. 111–159.Google Scholar
  3. 3.
    Singer, B. 1979. N-Nitroso alkylating agents: Formation and persistence of alkyl derivatives in mammalian nucleic acids as contributing factors in carcinogenesis. J. Natl. Cancer Inst. 62: 1329–1339.PubMedGoogle Scholar
  4. 4.
    Lawley, P.D. 1976. Carcinogenesis by alkylating agents. In: Chemical Carcinogens. C.E. Searle, ed. ACS Monograph Series no. 173. American Chemical Society: Washington, DC. pp. 83–244.Google Scholar
  5. 5.
    Rajewsky, M.F., R. Goth, O.D. Laerum, H. Biessmann, and D.F. Hulser. 1976. Molecular and cellular mechanisms in nervous system-specific carcinogenesis by N-ethyl-N-nitrosourea. In: Fundamentals in Cancer Prevention. Proc. 6th Int. Res. Symp. of the Princess Takamatsu Cancer Research Fund, Tokyo. P.N. Magee, S. Takayama, T. Sugimura, and T. Matsushima, eds. University Park Press: Baltimore. pp. 313–334.Google Scholar
  6. 6.
    Lawley, P.D. 1980. DNA as a target of alkylating carcinogens. Brit. Med. Bull. 36: 19–24.PubMedGoogle Scholar
  7. 7.
    Pegg, A.E., W. Perry, and R.A. Bennett. 1981. Effect of partial hepatectomy on removal of O 6-methylguanine from alkylated DNA by rat liver extracts. Biochem. J. 197: 195–201.PubMedGoogle Scholar
  8. 8.
    Margison, G.P., and A.E. Pegg. 1981. Enzymatic release of 7-methylguanine from methylated DNA by rodent liver extracts. Proc. Natl. Acad. Sci. 78: 861–865.PubMedCrossRefGoogle Scholar
  9. 9.
    Pegg, A.E. 1978. Enzymatic removal of O6-methylguanine from DNA by mammalian cell extracts. Biochem. Biophys. Res. Comm. 84: 166–173.PubMedCrossRefGoogle Scholar
  10. 10.
    Pegg, A.E., and B. Balog. 1979. Formation and subsequent excision of O 6-ethylguanine from DNA of rat liver following administration of diethylnitrosamine. Cancer Res. 39: 5003–5009.PubMedGoogle Scholar
  11. 11.
    Pegg, A.E. 1978. Dimethylnitrosamine inhibits enzymatic removal of 06-methylguanine from DNA. Nature 274: 182–184.PubMedCrossRefGoogle Scholar
  12. 12.
    Chetsanga, C.J., and T. Lindahl. 1979. Release of 7-methylguanine residues whose imidazole rings have béen opened from damaged DNA by a DNA glycosylase from Escherichia coli. Nucl. Acid Res. 6: 3673–3684.CrossRefGoogle Scholar
  13. 13.
    Pegg, A.E., and G. Hui. 1978. Formation and subsequent removal of 06-methylguanine from DNA in rat liver and kidney after small doses of dimethylnitrosamine. Biochem. J. 173: 739–748.PubMedGoogle Scholar
  14. 14.
    Bradford, M.M. 1976. A rapid and sensitive method for quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal. Biochem. 72: 248–254.PubMedCrossRefGoogle Scholar
  15. 15.
    Druckrey, H., R. Preussman, S. Ivankovic, and D. Schmähl. 1967. Organotrope carcinogene Wirkungen bei 65 verschiedenen N. Nitroso-Verbindungen an BD-Ratten. Z. Krebsforsch. 69: 103–201.PubMedCrossRefGoogle Scholar
  16. 16.
    Magee, P.N., R. Montesano, and R. Preussman. 1976. N-Nitroso compounds and related carcinogens. In: Chemical Carcinogens. C.E. Searle, ed. ACS Monograph Series no. 173. American Chemical Society: Washington, DC. pp. 491–625.Google Scholar
  17. 17.
    Swann, P.F., and A.E.M. McLean. 1971. Cellular injury and carcinogenesis. The effect of a protein-free, high carbohydrate diet on the metabolism of dimethylnitrosamine in the rat. Biochem. J. 124: 283–228.PubMedGoogle Scholar
  18. 18.
    Montesano, R., and P.N. Magee. 1974. Comparative metabolism in vitro of nitrosamines in various animal species including man. In: Chemical Carcinogenesis Essays. R. Montesano and L. Tomatis, eds. IARC Scientific publication no. 10. International Agency for Cancer Research: Lyons, France. pp. 39–56.Google Scholar
  19. 19.
    Pegg, A.E. 1980. Metabolism of N-nitrosodimethylamine. In: Molecular and Cellular Aspects of Carcinogen Screening Tests. R. Montesano, H. Bartsch, and L. Tomatis, eds. IARC Scientific publication no. 27. International Agency for Cancer Research: Lyons, France. pp. 3–22.Google Scholar
  20. 20.
    Pegg, A.E. 1980. Formation and subsequent repair of alkylation lesions in tissues of rodents treated with nitrosamines. Arch. Toxicol., Suppl. 3: 55–58.Google Scholar
  21. 21.
    Diaz Gomez, M.I., P.F. Swann, and P.N. Magee. 1977. The absorption and metabolism in rats of small oral doses of dimethylnitrosamine. Biochem. J. 164: 417–500.Google Scholar
  22. 22.
    Lindahl, T. 1976. New class of enzymes acting on damaged DNA. Nature 259: 64–66.PubMedCrossRefGoogle Scholar
  23. 23.
    Riazuddin, S., and T. Lindahl. 1978. Properties of 3-methyladenine DNA glycosylase from Escherichia coli. Biochemistry 17: 2110–2118.PubMedCrossRefGoogle Scholar
  24. 24.
    Brent, T.P. 1979. Partial purification and characterization of human 3-methyladenine DNA glycosylase. Biochemistry 18: 911–916.PubMedCrossRefGoogle Scholar
  25. 25.
    Cathcart, R., and D.A. Goldthwait. 1981. Enzymatic excision of 3-methyladenine and 7-methylguanine by a rat liver nuclear fraction. Biochemistry 20: 273–280.PubMedCrossRefGoogle Scholar
  26. 26.
    Laval, J., J. Pierre, and F. Laval. 1981. Release of free 7-methylguanine residues by cell extracts of Micrococcus luteus and Escherichia cola from alkylated DNA. Proc. Natl. Acad. Sci. 78: 852–855.Google Scholar
  27. 27.
    Singer, B., and T.P. Brent. 1981. Human lymphoblasts contain DNA glycosylase activity excising N-3 and N-7 methyl and ethyl purines, but not O6-alkylguanine or 1-alkyladenine. Proc. Natl. Acad. Sci. 78: 856–860.Google Scholar
  28. 28.
    Nemoto, N., and S. Takayama. 1974. Rapid loss of 7-methylguanine from liver nucleic acids in mice during the initial stage of liver carcinogenesis induced by DMN. Biochem. Biophys. Res. Comm. 58: 242–249.Google Scholar
  29. 29.
    Stumpf, R., G.P. Margison, R. Montesano, and A.E. Pegg. 1979. Formation and loss of alkylated purines from DNA of hamster liver after administration of dimethylnitrosamine. Cancer Res. 39: 50–54.PubMedGoogle Scholar
  30. 30.
    Lawley, P.D., and S.A. Shah. 1972. Methylation of ribonucleic acid by the carcinogens dimethyl sulphate, N-methyl-N-nitrosourea and N-methyl-N’-nitro-N-nitrosoguanidine: Comparisons of chemical analyses at the nucleoside and base levels. Biochem. J. 128: 117–132.Google Scholar
  31. 31.
    Olsson, M., and T. Lindahl. 1980. Repair of alkylated DNA in Escherichia coli. J. Biol. Chem. 255: 10569–10571.Google Scholar
  32. 32.
    Karren, P., T. Lindahl, and B. Griffin. 1979. Adaptive response to alkylating agents involves alteration in situ of O 6-methylguanine residues in DNA. Nature 280: 76–77.CrossRefGoogle Scholar
  33. 33.
    Renard, A., and W.G. Verly. 1980. A chromatin factor in rat liver which destroys 0 ethylguanine in DNA. FEBS Lett. 114: 98–102.PubMedCrossRefGoogle Scholar
  34. 34.
    Renard, A., L. Thibodeau, and W.G. Verly. 1978. O6-Ethylguanine excision from DNA of liver nuclei treated with ethylnitrosourea. Fed. Proc. 37: 1412.Google Scholar
  35. 35.
    Motesano, R., H. Brésil, G. Planche-Martel, G.P. Margison, and A.E. Pegg. 1980. Effect of chronic treatment of rats with dimethylnitrosamine on the removal of O 6-methylguanine from DNA. Cancer Res. 40: 452–458.Google Scholar
  36. 36.
    Rabes, H.M., R. Kerler, R. Wilhelm, G. Rode, and H. Riess. 1979. Alkylation of DNA and RNA by [1C]dimethylnitrosamine in hydroxyurea-synchronized regenerating rat liver. Cancer Res. 39: 4228–4236.PubMedGoogle Scholar
  37. 37.
    Buckley, J.D., P.J. O’Connor, and A.W. Craig. 1979. Pretreatment with acetylaminofluorene enhances the repair of 06-methylguanine in DNA. Nature 281: 403–404.PubMedCrossRefGoogle Scholar
  38. 38.
    Cooper, H.K., E. Hauenstein, G.F. Kolar, and P. Kleihues. 1978. DNA alkylation and neuro-oncogenesis by 3,3-dimethyl-l-phenyltriazine. Acta Neuropathol. ( Berl. ) 43: 105–109.PubMedCrossRefGoogle Scholar
  39. 39.
    Margison, G.P., N.J. Curtin, K. Snell, and A.W. Craig. 1979. Effect of chronic N,N-diethylnitrosamine on the excision of O 6-ethylguanine from rat liver DNA. Brit. J. Cancer 40: 809–813.PubMedCrossRefGoogle Scholar
  40. 40.
    Samson, L., and J. Cairns. 1977. A new pathway for DNA repair in Escherichia cola. Nature 267: 281–282.PubMedCrossRefGoogle Scholar
  41. 41.
    Schendel, P.F., M. Defais, P. Jeggo, L. Samson, and J. Cairns. 1978. Pathways of mutagenesis and repair in Escherichia cola exposed to low levels of simple alkylatiog agents. J. Bacteriol. 135: 466–475.PubMedGoogle Scholar
  42. 42.
    Lewis, J.G., and J.A. Swenberg. 1980. Differential repair of O4-methylguanine in DNA of rat hepatocytes and nonparenchymal cells. Nature 288: 185–187.PubMedCrossRefGoogle Scholar
  43. 43.
    Craddock, V.M. 1971. Liver carcinomas induced in rats by single administration of dimethylnitrosamine after partial hepatectomy. J. Natl. Cancer Inst. 47: 899–907.PubMedGoogle Scholar

Copyright information

© Plenum Press, New York 1983

Authors and Affiliations

  • Anthony E. Pegg
    • 1
  1. 1.Department of Physiology and Specialized Cancer Research Center, School of MedicinePennsylvania State UniversityHersheyUSA

Personalised recommendations