The long term objective of this project is to describe the molecular processes responsible for the induction of mutations when cells are treated with DNA-damaging mutagens. The immediate aims are to characterize the population of nucleotide sequence changes induced by ultraviolet light and related mutagens in chromosomal DNA of E. coli, to separately distinguish among them those that are targeted from those that are untargeted, and to determine the role of certain key gene functions in the production of the various types of mutations. This will be achieved by isolating mutations from lacI+ to lacI- for genes on an F' pro lac transferred to an independently treated Deltapro lac recipient, mapping these mutations to one of five large regions using deletions, transferring the mutations by recombination to an f1 lacI+ lacZ'Delta47 hybrid phage and sequencing them by means of the Sanger method. This will provide information about the capabilities of the altered replication complex, thought to exist in recA induced cells, when confronted with template defects of various kinds or normal DNA, and on the base-pairing capacity, if any, of the lesions. Understanding the mode of action of these mutagens is relevant to health concerns of two kinds. Environmental agents of this type may represent a health hazard, both as mutagens and carcinogens, but the magnitude of this risk can be fully assessed only when their mechanism of action is described in detail. Further, certain congenital diseases appear to be the consequence of DNA repair deficiencies, but these are poorly understood.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Microbial Physiology and Genetics Subcommittee 2 (MBC)
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University of Rochester
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Ozgenc, Ali I; Szekeres, Edward S; Lawrence, Christopher W (2005) In vivo evidence for a recA-independent recombination process in Escherichia coli that permits completion of replication of DNA containing UV damage in both strands. J Bacteriol 187:1974-84
Borden, Angela; O'Grady, Paul I; Vandewiele, Dominique et al. (2002) Escherichia coli DNA polymerase III can replicate efficiently past a T-T cis-syn cyclobutane dimer if DNA polymerase V and the 3' to 5' exonuclease proofreading function encoded by dnaQ are inactivated. J Bacteriol 184:2674-81
Vandewiele, D; Borden, A; O'Grady, P I et al. (1998) Efficient translesion replication in the absence of Escherichia coli Umu proteins and 3'-5' exonuclease proofreading function. Proc Natl Acad Sci U S A 95:15519-24
Horsfall, M J; Borden, A; Lawrence, C W (1997) Mutagenic properties of the T-C cyclobutane dimer. J Bacteriol 179:2835-9
Gentil, A; Le Page, F; Margot, A et al. (1996) Mutagenicity of a unique thymine-thymine dimer or thymine-thymine pyrimidine pyrimidone (6-4) photoproduct in mammalian cells. Nucleic Acids Res 24:1837-40
Lawrence, C W; Hinkle, D C (1996) DNA polymerase zeta and the control of DNA damage induced mutagenesis in eukaryotes. Cancer Surv 28:21-31
Szekeres Jr, E S; Woodgate, R; Lawrence, C W (1996) Substitution of mucAB or rumAB for umuDC alters the relative frequencies of the two classes of mutations induced by a site-specific T-T cyclobutane dimer and the efficiency of translesion DNA synthesis. J Bacteriol 178:2559-63
Lawrence, C W; Borden, A; Woodgate, R (1996) Analysis of the mutagenic properties of the UmuDC, MucAB and RumAB proteins, using a site-specific abasic lesion. Mol Gen Genet 251:493-8
Horsfall, M J; Lawrence, C W (1994) Accuracy of replication past the T-C (6-4) adduct. J Mol Biol 235:465-71
Lawrence, C W; Gibbs, P E; Borden, A et al. (1993) Mutagenesis induced by single UV photoproducts in E. coli and yeast. Mutat Res 299:157-63

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