MECHANISMS OF MUTAGENESIS BY AFLATOXIN AND OTHER AGENTS

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The fact that most chemical carcinogens are bacterial mutagens has strongly implicated DNA damage in carcinogenesis. The recent finding that a single base change is the only significant difference between a normal gene and its oncogenic derivative has supported the hypothesis that a specific mutation may be at least one step in the etiology of cancer. Thus understanding the process by which a carcinogen induces mutations may lead to the understanding of the basis of its carcinogenicity. The overall goal of the research proposed in this application is to elucidate how chemical carcinogens cause mutations in bacteria. The major focus is on the mutagenicity of the important human carcinogen aflatoxin B1, which makes bulky adducts to DNA. A second focus is on the mutagenicity of alkylating agents, such as N-methyl-N'-nitro-N-nitrosoguanidine and methyl methanesulfonate, which transfer simple alkyl groups to DNA bases. These two types of mutagenic damage are related by the similar nature of the bacterial functions for their repair, by the common intermediates that may be generated by these repair functions, and by the fact that their repair intermediates are likely to be themselves mutagenic. Genetic and biochemical methods will be used to determine the premutagenic lesions that these agents induce, the bacterial functions that repair them, how the lesions are converted to mutations, and what mutations result. The specific aims of this research are: 1. To generate and characterize defects in bacterial functions affecting both the accurate and mutagenic repair of the DNA lesions induced by aflatoxin B1. 2. To determine the effects of defects in known repair functions on the frequency and specificity of mutations induced by alkylating agents. The achievement of these aims will lead to the identification and characterization of the cellular activities that repair DNA damage and to the elucidation of how these activities may interact to produce mutations. Such knowledge may be directly relevant to understanding the consequences of DNA damage in higher organisms.