Stage-specific checkpoint signalling by ATM, ATR and DNA-PK safeguards oocyte genome integrity

Abstract

In somatic cells, DNA double-strand breaks (DSBs) are potentially catastrophic lesions that activate phosphatidylinositol 3-kinase-related kinase (PIKK) signalling to promote DNA repair or eliminate damaged cells. During meiosis, however, DSBs are deliberately generated as essential intermediates in homologous recombination, raising the question of how DNA damage signalling distinguishes programmed recombination from genome instability. To define how PIKK signalling is adapted to these distinct contexts, we resolved the function of the three PIKKs ATM, ATR and DNA-PK in physiological meiotic recombination and the response to postnatal DNA damage in mouse oocytes. Following postnatal irradiation, ATM functions as the dominant response kinase, with ATR and DNA-PK acting redundantly to eliminate damaged oocytes. In contrast, meiotic surveillance is mediated by ATR, with ATR removal rescuing oocyte loss in response to asynapsis and, independently, to persistent meiotic DSBs. Our findings demonstrate that DNA damage signalling is developmentally reconfigured during oogenesis and highlight distinct pathways of oocyte elimination that may ultimately inform strategies to maintain the ovarian reserve in mammals.