Infidelity of DNA Replication as a Basis of Mutagenesis

  • Thomas A. Kunkel
  • Roeland M. Schaaper
  • Elizabeth James
  • Lawrence A. Loeb
Part of the Basic Life Sciences book series (volume 15)


Errors in DNA replication must be very infrequent, so as not to alter essential genetic information; yet they must occur rarely so as to permit species divergence through mutations. On the basis of rates of appearance of spontaneous mutations, 10−7 to 10−11, DNA replication in vivo is assumed to be highly accurate (1). If one considers the multiplicity of genes demonstrated to affect mutation rates, it seems reasonable that this phenomenal accuracy is achieved through a multi-step process. We have focused on the fidelity by which DNA polymerases copy synthetic polynucleotides and natural DNA and the effects of mutagenic compounds on this accuracy. The underlying hypothesis is that infidelity by DNA polymerase, either on normal or damaged DNA, is a major determinant in mutagenesis.


Reversion Frequency Avian Myeloblastosis Virus Ethylmethane Sulphonate Adenosine Deaminase Deficiency Diol Epoxide 
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  1. 1.
    J.W. Drake, “The Molecular Basis of Mutation”, Holden Dag, San Francisco (1970).Google Scholar
  2. 2.
    Z.W. Hall and I.R. Lehman, An in vitro transversion by a mutationally altered T4 induced DNA polymerase, J. Biol. Chem., 36: 321 (1968).Google Scholar
  3. 3.
    N. Battula and L.A. Loeb, The infidelity of avian myeloblastosis deoxyribonucleic acid polymerase in polynucleotide replication, J. Biol. Chem., 249: 4086 (1974).PubMedGoogle Scholar
  4. 4.
    M.F. Goodman, R. Hopkins, and W.C. Gore, 2-Aminopurine-induced mutagenesis in T4 bacteriophage: A model relating mutation frequency to 2-aminopurine incorporation in DNA, Proc. Natl. Acad. Sci., USA, 74: 4806 (1977)PubMedCrossRefGoogle Scholar
  5. 5.
    L.A. Weymouth and L.A. Loeb, Mutagenesis during in vitro DNA synthesis, Proc. Natl. Acad. Scil, USA, 75: 1924 (1978).CrossRefGoogle Scholar
  6. 6.
    T.A. Kunkel and L.A. Loeb, On the fidelity of DNA replication: Effect of divalent metal ion activators and deoxyribonucleoside triphosphate pools on in vitro mutagenesis, J. Biol. Chem.; 254: 5718 (1979).PubMedGoogle Scholar
  7. 7.
    T.A. Kunkel and L.A. Loeb, The fidelity of mammalian DNA polymerases, Science, in press (1981).Google Scholar
  8. 8.
    T.A. Kunkel, R. Meyer, and L.A. Loeb, Single-strand binding protein enhances the fidelity of DNA synthesis in vitro, Proc. Natl. Acad. Sci., USA, 76: 6331 (1979).PubMedCrossRefGoogle Scholar
  9. 9.
    L.K. Tkeshelashvili, C.W. Shearman, R.A. Zakour, R.M. Koplitz, and L.A. Loeb, Effects of arsenic, selenium and chromium on the fidelity of DNA synthesis, Cancer Res., 40: 2455 (1980).PubMedGoogle Scholar
  10. 10.
    R.M. Schaaper, T.A. Kunkel, and L.A. Loeb, Depurination as a possible mutagenic pathway for cells, Gatlinburg Symposium on mutagenesis, in press (1981).Google Scholar
  11. 11.
    P.T. Englund, J.A. Huberman, T.M. Jovin, and A. Kornberg, Enzymatic synthesis of deoxyribonucleic acid. XXX. Binding of triphosphates to deoxyribonucleic acid polymerase, J. Biol. Chem., 244: 3038 (1969).PubMedGoogle Scholar
  12. 12.
    C. Bernstein, H. Bernstein, S. Mufti, and B. Strom, Stimulation of mutation in phage T4 by lesions in gene 32 and by thymidine imbalance, Mutat. Res., 16: 113 (1972).Google Scholar
  13. 13.
    G. Bjursall and P. Reichard, Effects of thymidine on deoxyribonucleoside triphosphate pools and deoxyribonucleic acid synthesis in Chinese hamster ovary cells, J. Biol. Chem., 248: 3904 (1973).Google Scholar
  14. 14.
    R.L. Davidson and E.R. Kaufman, Bromodeoxyuridine mutagenesis in mammalian cells is stimulated by thymidine and suppressed by deoxycytidine, Nature (London), 276: 722 (1978).CrossRefGoogle Scholar
  15. 15.
    A.R. Peterson, J.R. Landolph, H. Peterson, and C. Heidelberger, Mutagenesis of Chinese hamster cells is facilitated by thymidine and deoxycytidine, Nature (London), 276: 508 (1978).CrossRefGoogle Scholar
  16. 16.
    E.R. Giblett, J.E. Anderson, F. Cohen, B. Pollara, and H.J. Meuwissen, Adenosine deaminase deficiency in two patients with severly impaired cellular immunity, Lancet, 2: 1067 (1972).PubMedCrossRefGoogle Scholar
  17. 17.
    T. Lindahl and B. Nyberg, Rate of depurination of native deoxyribonucleic acid, Biochemistry, 11: 3610 (1972).PubMedCrossRefGoogle Scholar
  18. 18.
    T. Lindahl and A. Andersson, Rate of chain breakage at apurinic sites in double-stranded deoxyribonucleic acid, Biochemistry, 11: 3618 (1972).PubMedCrossRefGoogle Scholar
  19. 19.
    W.A. Deutsch and S. Linn, An apurinic DNA binding activity from cultured human fibroblasts that specifically inserts purines into depurinated DNA, Proc. Natl. Acad. Sci., USA, 76: 1089 (1979).CrossRefGoogle Scholar
  20. 20.
    P.D. Lawley and P. Brookes, Further studies on the alkylation of nucleic acids and their constituent nucleotides, Biochem. J., 89: 127 (1963).PubMedGoogle Scholar
  21. 21.
    B. Singer and T.P. Brent, Human lymphoblasts contain DNA glycosylase activity excising N-3 and N-7 methyl and ethyl purines but not 06-alkylguanines or 1-alkylguanines, Proc. Natl. Acad. Sci., USA, 78: 856 (1981).PubMedCrossRefGoogle Scholar
  22. 22.
    E. Bautz and E. Freese, On the mutagenic effect of alkylating agents, Proc. Natl. Acad. Sci., USA, 46: 1585 (1960).PubMedCrossRefGoogle Scholar
  23. 23.
    E.B. Freese, Transitions and transversions induced by depurinating agents, Proc. Natl. Acad. Sci., USA, 47: 540 (1961).PubMedCrossRefGoogle Scholar
  24. 24.
    P.D. Lawley and C.N. Martin, Molecular mechanisms in alkylation mutagenesis: Induced reversion of bacteriophage 4rII AP72 by ethylmethane sulphonate in relation to extent and mode of ethylation of purines in bacteriophage deoxyribonucleic acid, Biochem. J., 145: 85 (1975).Google Scholar
  25. 25.
    J.W. Drake and R.H. Baltz, The biochemistry of mutagenesis, Annu. Rev. Biochem., 45: 11 (1976).CrossRefGoogle Scholar
  26. 26.
    C.W. Shearman and L.A. Loeb, Depurination decreases fidelity of DNA synthesis in vitro, Nature, 270: 537 (1977).PubMedCrossRefGoogle Scholar
  27. 27.
    C.W. Shearman and L.A. Loeb, Effects of depurination on the fidelity of DNA synthesis, J. Mol. Biol., 128: 197 (1979).PubMedCrossRefGoogle Scholar
  28. 28.
    T.A. Kunkel, C.W. Shearman, and L.A. Loeb, Mutagenesis in vitro by depurination of cla174 DNA, Nature, in press (1981).Google Scholar
  29. 29.
    R.M. Schaaper and L.A. Loeb, Depurination causes mutations in SOS-induced cells, Proc. Natl. Acad. Sci., USA, 78: 1773 (1981).PubMedCrossRefGoogle Scholar
  30. 30.
    T. Lindahl, DNA glycosylases, endonucleases for apurinic/ apyrimidinic sites and base excision-repair, Prog. Nucleic Acid Res. Mol. Biol., 22: 135 (1979).Google Scholar
  31. 31.
    L.A. Loeb, T.A. Kunkel, and R.M. Schaaper, in: “Mechanistic Studies on DNA Replication and Genetic Recombination,” Vol. XIX, Academic Press, New York (1980), pp. 735–751.Google Scholar
  32. 32.
    M. Radman, Phenomenology of an inducible mutagenic DNA repair pathway in Escherichia coli: SOS repair hypothesis, in: “Molecular and Environmental Aspects of Mutagenesis,” L. Prakash, F. Sherman, M.W. Miller, C.M. Lawrence, and H.W. Taber, eds., Thomas, Springfield, IL (1974), pp. 128142.Google Scholar
  33. 33.
    E.M. Witkin, Ultraviolet mutagenesis and inducible DNA repair in Escherichia coli, Bacteriol. Rev., 40: 869 (1976).PubMedGoogle Scholar
  34. 34.
    P. Moore and B.S. Strauss, Sites of inhibition of in vitro DNA synthesis in carcinogen-and UV-treated X174 DNA, Nature, 278: 664 (1979).PubMedCrossRefGoogle Scholar
  35. 35.
    W.T. Hsu, E.J. Lin, R.G. Harvey, and S.B. Weiss, Mechanism of phage OX174 DNA inactivation by benzo[a]pyrene-7, 8-dihydrodiol-9, 10-epoxide, Proc. Natl. Acad. Sei., USA, 74: 3335 (1977).Google Scholar
  36. 36.
    J.M. Essigmann, R.G. Croy, A.M. Nadzan, W.F. Busby, V.N. Reinhold, G. BUchi, and G.N. Wogan, Structural identification of the major DNA adduct formed by aflatoxin B1 in vitro, Proc. Natl. Acad. Sci., USA, 74: 1870 (1977).PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1983

Authors and Affiliations

  • Thomas A. Kunkel
    • 1
  • Roeland M. Schaaper
    • 1
  • Elizabeth James
    • 1
  • Lawrence A. Loeb
    • 1
  1. 1.Gottstein Memorial Cancer Research Laboratory Department of Pathology SM-30University of WashingtonSeattleUSA

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