Spontaneous mutation mechanisms are important in the origins and progression of cancer, development of resistance of tumors to chemotherapeutic drugs, resistance of pathogenic microbes to antibiotics, and other medically significant problems. This proposal focuses on understanding the molecular mechanism of a DNA repair protein-dependent mutation pathway that causes drug-resistance mutations in the chromosomes of enterobacteria. E. coli is use as a model organism. We have discovered that the RecA and RecBCD recombination-repair proteins of E. coli are necessary for the accumulation of beta-lactam drug-resistant mutations in the E. coli chromosome. This implicate either an SOS DNA damage repair-response, or recombinational DNA repair, or both, in the mutation mechanism. To our knowledge, this is only the third example known of mutagenesis dependent on RecA and RecBCD. The first is from work on stationary-phase (""""""""adaptive"""""""") reversion of an episomal lac frameshift mutation in E. coli. Significant insights into the molecular mechanism of stationary-phase mutation in the lac system have been obtained. These provide unique and powerful entry into understanding the molecular mechanism of these chromosomal mutations, which will be exploited by the work proposed here, usin the well developed genetics of the E. coli model system. The goal of this project is to provide a complete description of the molecular mechanism of DNA repair-gene dependent chromosomal mutation to drug-resistance. The principles learned in this new model system may apply to chemotherapeutic drug-resistance to other antibiotic resistances, and to other mutations that may be caused or facilitated by mutational and DNA repair-related events during drug exposure.
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