biostudies-literatureKim SYNICHD NIH HHSFoundation for the National Institutes of HealthNIMH NIH HHSNCI NIH HHSNINDS NIH HHSU.S. Department of Health & Human Services | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development502-515https://www.ebi.ac.uk/biostudies/studies/S-EPMC6370889biostudies-literatureUnknown26(3)Platinum-based chemotherapies can result in ovarian insufficiency by reducing the ovarian reserve, a reduction believed to result from apoptosis of immature oocytes via activation/phosphorylation of TAp63α by multiple kinases including CHEK2, CK1, and ABL1. Here we demonstrate that cisplatin (CDDP) induces oocyte apoptosis through a novel pathway and that temporary repression of this pathway fully preserves ovarian function in vivo. Although ABL kinase inhibitors effectively block CDDP-induced apoptosis of oocytes, oocytic ABL1, and ABL2 are dispensable for damage-induced apoptosis. Instead, CDDP activates TAp63α through the ATR > CHEK1 pathway independent of TAp63α hyper-phosphorylation, whereas X-irradiation activates the ATM > CHEK2 > TAp63α-hyper-phosphorylation pathway. Furthermore, oCell death and differentiationTransient inhibition of p53 homologs protects ovarian function from two distinct apoptotic pathways triggered by anticancer therapies.PMC6370889P30 CA016058P50 HD07618850HD076188R01 CA154358R01 NS039475R01 HD064402R01 MH115939R01 NS089662R01 NS105640P50HD076188Kim SYSerna VANair DMKurita TRomero MWoodruff TKKoleske AJfalseTransient inhibition of p53 homologs protects ovarian function from two distinct apoptotic pathways triggered by anticancer therapies.Platinum-based chemotherapies can result in ovarian insufficiency by reducing the ovarian reserve, a reduction believed to result from apoptosis of immature oocytes via activation/phosphorylation of TAp63α by multiple kinases including CHEK2, CK1, and ABL1. Here we demonstrate that cisplatin (CDDP) induces oocyte apoptosis through a novel pathway and that temporary repression of this pathway fully preserves ovarian function in vivo. Although ABL kinase inhibitors effectively block CDDP-induced apoptosis of oocytes, oocytic ABL1, and ABL2 are dispensable for damage-induced apoptosis. Instead, CDDP activates TAp63α through the ATR > CHEK1 pathway independent of TAp63α hyper-phosphorylation, whereas X-irradiation activates the ATM > CHEK2 > TAp63α-hyper-phosphorylation pathway. Furthermore, o2019-01-01T00:00:00Z2019 Mar2026-07-14T14:55:15.89Z2025-04-05T20:37:36.513ZS-EPMC63708892998807510.1038/s41418-018-0151-2