The functions of a previously uncharacterized meiotic protein, MCMDC2, that is crucial for meiotic recombination and fertility in mouse.

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Sexual reproduction crucially depends on the generation of haploid cells from diploid cells by the specialized cell-division process of meiosis. Orderly segregation of chromosomes and the reduction of ploidy during meiosis require that homologous chromosomes find each other and become linked through the formation of crossovers in the first meiotic prophase. This demanding task requires a specially modified homologous recombination process that entails: (1) the active generation of large numbers of DNA double strand breaks, (2) the use of resulting DNA ends for homology search, and (3) the repair of the DNA breaks with the preferential use of homologous chromosomes, as opposed to sister chromatids, as repair templates. Despite extensive research, key questions of meiotic recombination are unanswered. What are the key molecular differences between meiotic and mitotic recombination, and how do these differences help to ensure that homologous chromosomes find each other with high fidelity even in large repeat-rich mammalian genomes?One key impediment to answering these questions has been the incomplete knowledge of the tool-kit of meiotic recombination. In a screen, we identified an uncharacterized potential DNA helicase, MCMDC2, that is preferentially expressed in meiosis. Importantly, we found that MCMDC2 is essential for meiotic homology search. Hence, I propose to study MCMDC2 to gain novel insight into the molecular basis of meiotic recombination.In brief, extensive mouse genetics involving Mcmdc2 knockout analysis will be used to define the steps in meiotic recombination that require MCMDC2, and to test the hypothesis that MCMDC2 is primarily needed for inter-homologue recombination as opposed to inter-sister recombination. Complementing this approach, we will examine the localization and the behaviour of MCMDC2 relative to other recombination proteins both in wild-type and various meiotic recombination defective mutant mice. Additionally, we will attempt to map MCMDC2´s interacting partners using biochemistry and yeast two-hybrid assay. The combination of these approaches will allow us to define the biological function of MCMDC2 in meiosis, and will pave the way for future experiments addressing the mechanistic role of MCMDC2 in recombination. Given the importance of MCMDC2, I expect that the proposed work will provide new answers to key questions of meiotic recombination, and will significantly contribute to the understanding of how homologous chromosomes recognize each other, and how genome integrity is maintained during meiosis in the germline. Key meiotic recombination genes are central to fertility and genome health, and their misexpression and mutations are contributing factors in some cancers. Hence, the proposed work has obvious medical implication too.