Extensive homologous recombination safeguards oocyte genome integrity in mammals

Meiosis in mammalian oocytes is interrupted by a prolonged arrest at the germinal vesicle stage, during which oocytes have to repair DNA lesions to ensure genome integrity or otherwise undergo apoptosis. The FIRRM/FLIP-FIGNL1 complex dissociates RAD51 from the joint DNA molecules in both homologous recombination (HR) and DNA replication. However, as a type of non-meiotic, non-replicative cells, whether this RAD51-dismantling mechanism regulates genome integrity in oocytes remains elusive. Here, we show that FIRRM/FLIP is required for disassembly of RAD51-filaments and maintenance of genome integrity in oocytes. Deletion of FIRRM in oocytes leads to formation of massive nuclear RAD51 foci in oocytes of primordial follicles and activated follicles in mice. These RAD51 foci colocalize with the sites of DNA damage repair, as indicated by RPA2 and EdU, suggesting substantial DNA damage and extensive HR in oocytes. Especially in fully-grown FIRRM-deleted oocytes, RAD51 forms a net-like structure. As a consequence, FIRRM-deleted females are infertile due to aberrant homologous chromosome segregation at metaphase I and primordial follicle insufficiency at young adulthood. Hence, our study demonstrates the physiological importance of HR in maintaining genome integrity in oocytes.