Error Prone DNA Synthesis and Oncogene Mutagensis

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DESCRIPTION: (PROVIDED BY APPLICANT) There is evidence that "spontaneous" mutations in normal cells may result in large part from the operation of recently discovered mutagenic DNA polymerases rather than as a consequence of errors made by the major replicating system. Mutation is therefore the result of the interaction of the replicative and auxiliary DNA polymerases, the mismatch DNA repair system and the proofreading exonucleases. The different components may play more than one role, for example, as both structural and functional components of the replicative apparatus. It is the goal of the proposed work to determine the role of the auxiliary polymerases and to understand how they interact with the various components of the replication system. We wish to test the hypothesis that the mismatch repair proteins play a direct role in providing the auxiliary polymerases access to the DNA growing point. We want to determine the exact sites of interaction between the E. coli proofreading and DNA polymerase subunits and to understand how proofreading polymerization and mismatch repair interact. We propose to study the interactions between the polymerases and other relevant genes to determine how the cell "decides" which polymerase to use. We suppose that mutation in organisms is not an inevitable consequence of DNA replication. For unknown reasons, cells have arranged both to mutate and to control their mutation rate and have assigned particular enzymes to this job. If this view is confirmed, the error-prone polymerases provide an entirely new target for chemotherapy. Blocking the action of the error-prone polymerases should not stop replication. However, mutational cascades, such as those leading to tumor drug resistance, should be inhibited by such a block.