Xrcc5/Ku80 is required for the repair of DNA damage in fully grown meiotically arrested mammalian oocytes

Mammalian oocytes spend most of their life in a unique state of cell cycle arrest at meiotic prophase I, during which time they are exposed to countless DNA-damaging events. Recent studies have shown that DNA double-strand break repair occurs predominantly via the homologous recombination (HR) pathway in small non-growing meiotically arrested oocytes (primordial follicle stage). However, the DNA repair mechanisms employed by fully grown meiotically arrested oocytes (GV-stage) have not been studied in detail. Here we established a conditional knockout mouse model to explore the role of Ku80, a critical component of the nonhomologous end joining (NHEJ) pathway, in the repair of DNA damage in GV oocytes. GV oocytes lacking Ku80 failed to repair etoposide-induced DNA damage, even when only low levels of damage were sustained. This indicates Ku80 is needed to resolve DSBs and that HR cannot compensate for a compromised NHEJ pathway in fully-grown oocytes. When higher levels of DNA damage were induced, a severe delay in M-phase entry was observed in oocytes lacking XRCC5 compared to wild-type oocytes, suggesting that Ku80-dependent repair of DNA damage is important for the timely release of oocytes from prophase I and resumption of meiosis. Ku80 was also found to be critical for chromosome integrity during meiotic maturation following etoposide exposure. These data demonstrate that Ku80, and NHEJ, are vital for quality control in mammalian GV stage oocytes and reveal that DNA repair pathway choice differs in meiotically arrested oocytes according to growth status.

Automated summary

Mammalian oocytes in the primordial follicle stage primarily use the homologous recombination pathway for DNA repair, while fully grown oocytes in the GV stage rely on the nonhomologous end joining pathway. The loss of Ku80 in fully grown oocytes leads to the inability to repair DNA damage and delays the entry into M-phase, indicating the importance of Ku80-dependent repair in meiotic progression. Furthermore, Ku80 is critical for chromosome integrity during meiotic maturation after DNA damage. These findings highlight the significance of Ku80 and NHEJ in maintaining quality control in mammalian oocytes.