Reduced autophagy contributes to inefficient DNA damage repair in mouse oocytes

[EMBARGOED UNTIL 8/1/2023] The DNA damage is a major problem that, in somatic cells, leads to mutagenesis and premature aging. However, this is not the case in fully differentiated germ cells. Why DNA damage repair (DDR) machinery is not robust in fully grown mammalian oocytes is unknown. Using mouse oocyte as a model system, we found that DDR is not functional in oocytes, leading to the development of aneuploid oocytes. Our data indicate that oocyte failure to repair damaged DNA is due to the inability of DDR protein, RAD51, to access the altered, "closed" chromatin conformation in DNA-damaged oocytes. Our data also reveal that, unlike somatic cells, oocytes fail to activate autophagy(definition) in response to DNA damage, which is the cause of altered chromatin conformation and inefficient DDR. Importantly, autophagy induction rescued DDR function and decreased aneuploidy in both DNA-damaged oocytes and oocytes from maternally aged mice which are prone to severe DNA damage. Our findings provide evidence that reduced autophagy contributes to weakened DDR in mammalian oocytes, especially in those of females with advanced reproductive age. Thus, oocyte autophagy management could provide a new aneuploidy treatment option for patients of advanced reproductive age in human assisted reproductive therapy.