Insufficient telomeric DNA damage response promotes chromosomal instability in aged oocytes.

Increased chromosomal instability impairs oocyte quality, contributing to female reproductive aging. The telomeric DNA damage response (DDR) is essential for genomic stability; however, how oocytes respond to telomeric damage remains elusive. Here, we observed that aged human germinal vesicle (GV) oocytes accumulated telomeric DNA damage. We next established a telomeric DNA damage model with CRISPR/Cas9 in mouse oocytes, which exhibited increased chromosome instability and impaired meiotic maturation. Furthermore, telomeric DNA damage in oocytes did not initiate telomere fusion but rather accelerated telomere movement and triggered break-induced telomere synthesis (BITS). Mechanistically, RPA32 and RAD51 were recruited to damaged telomeres, and contributed to BITS along with ATR and PARP1. However, telomeric DNA damage recruited few RNF8 in fully grown oocytes, possibly impeding the 53BP1 recruitment. Despite minimal changes in the overall activity of RAD51-promoted DNA repair in GV oocytes with maternal age, this DDR machinery was preferentially involved in non-telomeric regions in aged oocytes. Consequently, upon encountering telomeric DNA damage, aged oocytes might undergo insufficient telomeric DDR and BITS. Together, our study illustrates that telomeric DDR recruits key factors, such as RAD51, to activate BITS, and that insufficient telomeric DDR increases chromosomal instability in aged oocytes.