The molecular basis of HORMAD1 dependent coordination of key meiotic processes

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Meiotic crossover (CO) formation between homologous chromosomes (homologues) entails DNA double strand break (DSB) formation, homology search using DSB ends, and synaptonemal complex (SC) formation coupled with DSB repair. Meiotic progression must be prevented until DSB repair and SC formation are completed to avoid formation of gametes with abnormal genomes. Despite its im-portance, meiotic progression control is poorly understood. Recently, we identified HORMAD1 as a central player in the coordination of meiotic progression and CO formation associated processes. HORMAD1 ensures that sufficient numbers of processed DSBs are available for homology search. HORMAD1 is needed for normal SC formation. Finally, HORMAD1 plays a critical role in meiotic pro-phase checkpoints in both sexes, a function that is probably performed through recruiting and adapt-ing mitotic DNA damage response (DDR) proteins for meiosis specific checkpoint functions. HOR-MAD1 is a key guardian of the germline, since HORMAD1 is essential for the elimination of both DSB repair- and SC-defective oocytes. To gain novel insights into the coordination of meiotic progression and CO associated meiotic processes, we will study the molecular basis of HORMAD1 functions and the role of DDR proteins in HORMAD1 dependent processes trough genetics (using DDR knockout and our Hormad1-/- mice) and biochemistry (HORMAD1 interactions and regulation). Given that an-euploidies often originate from meiotic prophase errors in humans this work will have important impli-cations in human reproductive biology as well.