We propose to investigate the biochemical basis of mutagenesis. Bacteriophage T4, have normal and aberrant DNA polymerases (mutators and antimutators), will be used as a model system for study. Experiments, in vitro and in vivo, are designed to measure individual steps in the mutational pathways A:T yields ( reversibily) G:C using the base analogues 2-aminopurine and 5-bromodeoxyuridine as biochemical and genetic probes. A model requiring base mispairing and deoxynucleoside triphosphate pool size perturbations is proposed to account for base analogue induced mutagenesis. The model provides a general framework to relate deoxynucleoside triphosphate pool size measurements in vivo, made in T4 mutator, wild type, and antimutator genetic backgrounds, to measurements in vitro for nucleotide analogue mispairing frequencies. These experimental results in concert with model based predictions will allow us to test models of DNA synthesis fidelity in a stringent quantitative manner. The experiments should provide a clearer picture of how organisms edit errors which occur during DNA synthesis. Thus, in a general sense, this proposal is concerned with cellulose mechanisms used to maintain genetic integrity through successive generations. The potential significance of the results should have broad application in the areas of carcinogenesis, ageing, and evolution.
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