The goal of our research is to provide a cellular and molecular understanding of human Rad51-mediated DNA repair. The catalytic activity of Rad51 is of fundamental importance to homologous recombination, a process required for maintenance of genome integrity under both normal metabolic conditions and in response to mutagenic stress. Studies in this revised proposal are directed at understanding how Rad51 function is regulated through specific protein-protein interactions. In revised Aim 1 we will use RNAi and cell-based methods to explore the functional relationship of Rad51 with other proteins known to assist its cellular activity. We have found that Rad51 stability and degradation are regulated through its interaction with the Rad51 paralog protein, Rad51C. Additionally, our data suggest that Rad51 degradation is compartmentalized within the cell, and work in this Aim will address how this is regulated. Work in revised Aim 3 focuses on analysis of specific mutant proteins to advance our understanding of the biochemical processes that underlie Rad51-mediated DNA repair. We will take advantage of our recently published methodology using RNAi to analyze the function of mutant Rad51, Rad51C and Xrcc3 proteins in human cells. Biochemical studies of mutant proteins will also be included to provide further mechanistic insight into the cellular requirements of specific protein functions.
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