Stage-specific checkpoint signalling by ATM, ATR and DNA-PK safeguards oocyte genome integrity
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…
In mammalian females, the integrity of the oocyte genome is protected by specialized checkpoint signaling pathways, even when DNA double-strand breaks (DSBs) are purposefully induced during meiosis. These DSBs are crucial for homologous recombination, yet they pose a risk for genomic instability. To understand how PIKK signaling differentiates between intentional recombination and unwanted damage, researchers examined the roles of ATM, ATR, and DNA-PK in mouse oocytes.
Postnatal irradiation revealed that ATM is the primary kinase, with ATR and DNA-PK functioning redundantly to clear damaged oocytes. During meiosis, ATR-mediated surveillance is responsible for eliminating oocytes with unsynapsed homologs or persistent DSBs. Notably, removing ATR does not rescue oocyte loss in ATM-deficient oocytes, but co-depleting ATR and DNA-PK only partially restores viability, indicating an ATR-independent mechanism for oocyte elimination.
These findings demonstrate that the oocyte's response to DNA damage is developmentally adapted and suggest potential strategies to preserve ovarian function in mammals.
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