EXOCYCLIC ADDUCTS--SITE-SPECIFIC MUTAGENESIS

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The objectives of this research are to determine the mutational spectra of lesions produced in mammalian cells and bacteria when exocyclic adducts are introduced at specific genomic sites and to delineate recombinational events as they relate to mutagenesis produced by such adducts. DNA adducts may be removed by the concerted action of repair enzymes acting throughout the genome. When this process is incomplete, the stage is set for errors in DNA replication that lead to mutation. We intend to inves- tigate several aspects of DNA repair as it relates to the structure and function of exocyclic adducts. We have developed experimental systems, using SV40-based shuttle plasmid vectors, by which the mutagenic spectra of selected DNA adducts can be determined. This approach allows us to examine the sequence specificity of mutational reactions with particular reference to "hot spots" and proto- oncogenes. Using these systems, which reflect forward mutagenic events produced by a single species of DNA adduct and by correlating our studies with the results of molecular modeling and 2D-NMR experiments, we hope to define structure-activity relationships that will assist in elucidating mechanisms of chemical mutagenesis and, possibly, predict mutagenic effects for certain classes of chemical carcinogens.