Changes in DNA repair compartments and cohesin loss promote DNA damage accumulation in aged oocytes.

Oocyte loss, a natural process that accelerates as women approach their mid-30s, poses a significant challenge to female reproduction. Recent studies have identified DNA damage as a primary contributor to oocyte loss, but the mechanisms underlying DNA damage accumulation remain unclear. Here, we show that aged oocytes have a lower DNA repair capacity and reduced mobility of DNA damage sites compared to young oocytes. Incomplete DNA repair in aged oocytes results in defective chromosome integrity and partitioning, thereby compromising oocyte quality. We found that DNA repair proteins are arranged in spatially distinct DNA repair compartments that form during the late stages of oocyte growth, accompanied by changes in the activity of DNA repair pathways. We demonstrate alterations in these compartments with age, including substantial changes in the levels of key DNA repair proteins and a shift toward error-prone DNA repair pathways. In addition, we show that reduced cohesin levels make aged oocytes more vulnerable to persistent DNA damage and cause changes in DNA repair compartments. Our study links DNA damage accumulation in aged oocytes, a leading cause of oocyte loss, to cohesin deterioration and changes in the organization, abundance, and response of DNA repair machinery. [Display omitted] • Aged oocytes accumulate DNA damage and have a reduced capacity for DNA repair • DNA repair proteins are organized into distinct nuclear DNA repair compartments • Aged oocytes show changes in DNA repair machinery, favoring error-prone repair • Age-related cohesin loss also contributes to reduced capacity for DNA repair Oocytes accumulate DNA damage with advancing maternal age, leading to their eventual death and loss of reproductive potential. Sharma et al. show that aged oocytes accumulate DNA damage due to reduced DNA repair capacity, changes in DNA repair compartments, loss of cohesin, and a shift toward error-prone repair pathways. [ABSTRACT FROM AUTHOR]