Oocytes can efficiently repair DNA double-strand breaks to restore genetic integrity and protect offspring health

Abstract

<jats:p>Female fertility and offspring health are critically dependent on an adequate supply of high-quality oocytes, the majority of which are maintained in the ovaries in a unique state of meiotic prophase arrest. While mechanisms of DNA repair during meiotic recombination are well characterized, the same is not true for prophase-arrested oocytes. Here we show that prophase-arrested oocytes rapidly respond to γ-irradiation–induced DNA double-strand breaks by activating Ataxia Telangiectasia Mutated, phosphorylating histone H2AX, and localizing RAD51 to the sites of DNA damage. Despite mobilizing the DNA repair response, even very low levels of DNA damage result in the apoptosis of prophase-arrested oocytes. However, we show that, when apoptosis is inhibited, severe DNA damage is corrected via homologous recombination repair. The repair is sufficient to support fertility and maintain health and genetic fidelity in offspring. Thus, despite the preferential induction of apoptosis following exogenously induced genotoxic stress, prophase-arrested oocytes are highly capable of functionally efficient DNA repair. These data implicate DNA repair as a key quality control mechanism in the female germ line and a critical determinant of fertility and genetic integrity.</jats:p>

DNA Damaged Induced Cell Death in Oocytes

“…Using inhibitors of RAD51 prevented the HR-based repair of DSBs following γ-irradiation with 0.45Gy. This treatment resulted in depletion of primary oocyte numbers and increased apoptosis of oocytes despite the lack of TAp63α [100]. The same study reported that large numbers of mature oocytes could be ovulated in TAp63 −/− mice exposed to 0.1 Gy, however, only low numbers could be ovulated when these mice were exposed to 0.45 Gy.…”

“…Finally, Stringer et al investigated the effect of DNA repair mechanisms in damaged oocytes directly [100]. They observed a dose-dependent increase in nuclear phosphorylated ATM kinase, the occurrence of γH2AX and recruitment of RAD51 to the location of DNA damage.…”

Applying Single-Cell Analysis to Gonadogenesis and DSDs (Disorders/Differences of Sex Development)

“…In addition to age, other factors can deplete the ovarian reserve, resulting in an early menopause. These factors include smoking, cancer, environmental pollutants and chemotherapeutic drugs [ 170 ]. Understanding the mechanisms of the ovarian ageing is crucial for predicting and preventing ovarian loss and extending fertility among women.…”

Double-strand breaks can induce DNA replication and damage amplification in G2 phase-like oocytes of mice

“…These fully grown oocytes are termed SN oocytes whereas the growing oocytes are termed non-SN (NSN) oocytes (22). For the NSN and SN oocytes, both endogenous metabolites and exogenous factors can induce DSBs in their nuclear genome (23)(24)(25)(26), but whether DSBs in growing NSN and fully grown SN oocytes could be the contributing factor of CGR hasn't be analyzed. Our previous works showed Rad51 participated in the repair of oocyte DSBs (27), in this study we further analyzed the features of DSB repair in oocytes which would be new clues of CGR formation in germ cells and somatic cells.…”