DNA damage response signaling in oocytes from an oncofertility perspective

Abstract The remarkable advances in cancer therapies significantly enhance the survival rates and longevity of cancer patients. Among childhood, adolescent, and young adult female cancer survivors, however, anti-cancer agents frequently cause primary ovarian insufficiency (POI), early menopause, and infertility, primarily due to the depletion of the ovarian reserve. Oocytes, the female germ cells, exhibit a notable susceptibility to DNA damage, given that they remain in meiotic arrest of prophase I for prolonged durations from months to years, which increases the risks of accumulating DNA damage overtime. To counteract this, a tightly controlled DNA damage response (DDR) signaling ensures that only oocytes with an intact genome progress to ovulation, fertilization, and next generations. Chemotherapeutic anti-cancer agents, including doxorubicin, cisplatin, cyclophosphamide, along with irradiation, elicit DNA damage via various mechanisms, including DNA crosslinking, single and double-strand DNA breaks, and oxidative stress. The genotoxic insults activate DDR in the oocytes, which detect and repair DNA damage or initiate apoptosis to eliminate impaired oocytes. Although several protein molecules such as DNA damage-sensing kinases, checkpoint kinases, p53 family transcription factors, and pro-apoptotic molecules, have been discovered, the precise mechanisms of DDR in determining the fate of oocytes, particularly how they differ from those in somatic cells and cancer cells, remain poorly understood. From an oncofertility perspective, the current review analyzes the molecular mechanisms of anti-cancer agent-induced DDR in oocytes and discuss knowledge gaps and urgent future research directions for preserving the ovarian reserve, fertility, and endocrine functions of young female cancer patients.