The basis objective of this program is to understand in detail mutational processes, including the mechanisms by which mutagens induce mutations and also the pathways that result in spontaneous mutations. Towards this end we have developed and are continuing to develop systems in E. coli which allow the determination of mutagenic specificity at a high degree of resolution. Because of the presence of carcinogens in the environment, it is of practical importance to understand the manner in which carcinogenic agents cause mutations that can lead to cancer. We are investigating the specificity of mutations induced by ultraviolet light, benzo(a)pyrene, N-acetoxy-2-fluorenylacetamide, aflatoxin B1, 4-nitroquinoline-1-oxide, in addition to other environmental carcinogens. The research plan combines genetics and biochemistry, in that mutations are analyzed with a variety of genetic systems prior to selecting representative mutations to analyze by DNA sequencing. In addition to analyzing lacI nonsense mutations, we are employing selection systems in lacI that are specific for +1 and -1 frameshifts and for deletions. By understanding the specificity of mutagenesis, we hope to be able to pinpoint specific premutational lesions resulting from carcinogens binding to DNA and to elucidate the pathways that lead to mutations. Analysis of repair deficient and mutator strains should help identify pathways involved in generating spontaneous mutations.
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