Local DNA synthesis is critical for DNA repair during oocyte maturation

Abstract

ABSTRACT Mammalian oocytes can be very long-lived cells and thereby are very likely to encounter DNA damage during their lifetime. Defective DNA repair may result in oocytes that are developmentally incompetent or give rise to progeny with congenital disorders. During oocyte maturation, damaged DNA is repaired primarily by non-homologous end joining (NHEJ) or homologous recombination (HR). Although these repair pathways have been studied extensively, the associated DNA synthesis is poorly characterized. Here, using porcine oocytes, we demonstrate that the DNA synthesis machinery is present during oocyte maturation and dynamically recruited to sites of DNA damage. DNA polymerase δ is identified as being crucial for oocyte DNA synthesis. Furthermore, inhibiting synthesis causes DNA damage to accumulate and delays the progression of oocyte maturation. Importantly, inhibition of the spindle assembly checkpoint (SAC) bypassed the delay of oocyte maturation caused by DNA synthesis inhibition. Finally, we found that ∼20% of unperturbed oocytes experienced spontaneously arising damage during maturation. Cumulatively, our findings indicate that oocyte maturation requires damage-associated DNA synthesis that is monitored by the SAC. This article has an associated First Person interview with the first author of the paper.