Regulation of an Error-Prone Polymerase

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DESCRIPTION (provided by applicant): Genomic stability is vital to the health of the organism and the preservation of the species. This stability is threatened by DNA damage from endogenous and exogenous sources; such damage can cause mutations that lead to cancer and genetic disorders. To cope with DNA damage all organisms have both damage specific and general DNA repair pathways. This arsenal includes the newly-discovered Y-family DNA polymerases that can replicate damaged DNA. However, these polymerases are highly error-prone, making frequent errors even when replicating undamaged DNA. If the mutagenic activities of these polymerases are not controlled, they could become a potent source of genetic instability. The goal of this research project is to elucidate the cellular pathways that regulate error-prone DNA polymerases. The approach taken here focuses on DNA polymerase IV from the bacterium Escherichia coli as a model. E. coli's DNA polymerase IV is very closely related to the error-prone polymerases that are active in higher organisms, including humans. The mechanisms by which this simple bacterium controls the activity of Pol IV may provide a paradigm for similar mechanisms in all organisms. A number of cellular factors that affect Pol IV have already been identified. The research proposed will establish how these control the abundance and the activity of Pol IV. The specific aims are: (1) to determine how the abundance of Pol IV is regulated; (2) to establish how the mutagenic activity of Pol IV is regulated; (3) to identify and characterize protein interactions that affect Pol IV.