Female fertility declines with age due to reduced ovarian reserves and oocyte quality. A recent genome-wide association study of 70,000 women strongly links ovarian ageing and age of natural menopause to diminished DNA repair machinery (1). Interestingly, the ovarian reserve is protected from DNA damaging insults in apoptosis-resistant mice, unlike wildtypes, suggesting the existence of robust oocyte DNA repair mechanisms (2). Further studies demonstrated double-stranded DNA damage repair (ds-DDR) is critical for maintaining the ovarian reserve (3). For example, women carrying BRCA mutations have decreased ovarian reserve for age, due to the accumulation of unrepaired DNA-damage (4). While ds-DDR in oocytes is well-studied, less is known about the link between single-strand DNA-damage repair (ss-DDR) mechanisms and ovarian-aging (5).
The importance of the ss-DDR for oocyte survival was evaluated by inhibiting ss-DDR proteins PARP1/2 with Olaparib for 28-days in postnatal day (PN)60 C57BL6/J mice (n=8/group), resulting in a 50% depletion of primordial follicles (p<0.01) versus vehicle-controls. In contrast, inhibiting key ds-DDR protein, Rad51, for 28-days did not affect primordial follicle numbers. This highlights critical role of ss-DDR in protecting oocytes from intrinsic DNA-damage and apoptosis.
Furthermore, conditional loss of Xrcc1 (key Base Excision Repair protein) in mouse oocytes using Gdf9-Cre recombinase, led to depletion of primordial follicle oocytes by 47% (p<0.01; n=8/group) and accelerated the age-associated decline in growing follicles and ovulated oocytes at PN50 and PN300 versus wildtype littermates (p<0.05). However, fertility in these mice was unchanged between genotypes, with no change in fertile-lifespan, litter-size, and offspring-weight at PN5 and PN20.
Together, these data suggest for the first time that ss-DDR mechanisms are important for oocyte survival and maintenance of the primordial follicle pool during aging. Ongoing studies are exploring how primordial and growing follicles respond to exogenous DNA damaging insults in the context of genetic loss of Xrcc1.