That a single mutation can change a normal gene into its oncogenic derivative demonstrates the potential importance of mutagenic processes in the etiology of cancer. Thus, understanding how a carcinogen induces mutations may elucidate the basis of its carcinogenicity. The goal of this project is to determine how chemical carcinogens cause mutations, using bacteria as a model system. The research focuses on the mechanisms of mutagenesis of a few environmentally or medically significant genotoxic agents that cause representative classes of DNA damage. Genetic and biochemical methods are used to determine what DNA lesions are induced, how they may be repaired, which give rise to mutations, what cellular functions participate in the mutagenic process, and what mutations result.
The specific aims are: 1. To investigate the mechanism of mutagenesis of aflatoxin Bl, which makes bulky lesions to DNA. The effects of defects in bacterial functions affecting both the accurate and mutagenic repair of aflatoxin-induced DNA lesions will be characterized. The mutagenic potential of defined DNA lesions generated in vitro by a direct-acting aflatoxin analog will be determined. 2. To identify the major mutagenic lesions induced by halogenated hydrocarbons. The miscoding lesions demonstrated to be induced by 1,2-dibromoethane will be identified biochemically. Pathways for the repair of these lesions and their induction by other halogenated hydrocarbons will be examined 3. To investigate the mutagenic and toxic potential of the DNA lesions ' induced by the chemotherapeutic agent, cis- diamminedichloroplatinum II. The contribution of repair intermediates to the toxicity and mutagenicity of this agent will be determined.
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