Infidelity of DNA Replication as a Basis of Mutagenesis
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.
KeywordsReversion Frequency Avian Myeloblastosis Virus Ethylmethane Sulphonate Adenosine Deaminase Deficiency Diol Epoxide
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- 1.J.W. Drake, “The Molecular Basis of Mutation”, Holden Dag, San Francisco (1970).Google Scholar
- 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
- 7.T.A. Kunkel and L.A. Loeb, The fidelity of mammalian DNA polymerases, Science, in press (1981).Google Scholar
- 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
- 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.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
- 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
- 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
- 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.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.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
- 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