Homologous recombination is the only error-free system to repair DNA double-strand breaks. In meiosis, homologous recombination also provides temporal association between pairs of homologous chromosomes allowing their orderly segregation to opposite poles of dividing nuclei. This has a direct impact on faithful haploidization of a genome versus generation of aneuploidy. Indeed, failure of proper homologous chromosome segregation leads to infertility and severe aneuploid-based birth defects such as Down, Klinefelter, Edwards and Turner syndromes. At the center of the homologous recombination pathway is the step of strand invasion catalyzed by the ubiquitous Rad51 and the meiotic specific Dmcl recombinases. The proper functions of the recombinases require interaction with accessory proteins. Our central hypothesis is that two accessory proteins, Hop2 and Mndl, are essential for normal progression of homologous recombination and homologous chromosome segregation in mammalian meiosis. In part this may be explained by Hop2 and Mndl forming a heterodimer that stimulates strand invasion promoted by Dmcl and Rad51. In this proposal, we will use genetic and biochemical approaches to test this hypothesis and address fundamental questions about Mnd1 and Hop2 in higher eukaryotes: what are the structural determinants of the Hop2/Mnd1-Dmc1/Rad51 cooperation, and when and how do Mndl and Hop2 regulate the progression of homologous recombination in mammalian meiotic cells? Additionally, an important goal is to determine whether Hop2 by itself can function as a recombinase. If confirmed, our results will position Hop2 as the only ATP-independent meiotic recombinase and define a new pathway of DSB repair distinct from those promoted by Dmcl and Rad51. Through defining the roles of accessory proteins, the broader implication of our studies is to understand the contribution of homologous recombination in preventing homologous chromosome segregation defects leading to infertility and aneuploidy in humans.
Our results will help to understand the role of recombination, and its regulation in organismal health. We will provide new insights into the mechanisms that direct DNA recombination repair and proper homologous chromosome segregation in mammals. This information is necessary to delineate the root causes of infertility and the large number and increasing incidence of birth defects associated with aneuploidy.
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