Inhibition of Mutation: A Novel Approach to Preventing and Treating Cancer

摘要

The goal of this proposal is to identify the proteins in human cells that are responsible for mutagenesis. Specific biochemical pathways are responsible for introducing mutation to the genome. Using drug(s) to inhibit one or more of these proteins and thereby prevent cancer is a novel and unique cancer prevention approach. Using a yeast deletion strain library we developed and implemented high-throughput screens to identify genes involved in mutation. Using this approach we identified all of the genes required for mutation induced by DNA damage resulting from ultraviolet light and methylmethane sulfonate. Most notably the screens identified a novel pathway of induced mutation involving regulation of nucleotide substrates for a replicative DNA polymerase in addition to identifying the known pathways of induced mutation involving the error prone translesion polymerases. Future work will involve further characterization of the novel mutation pathway as well as additional screens using different damage conditions and selections.