Document Type

Article

Publication Date

10-20-2023

Keywords

JMG, Female, Animals, Mice, Checkpoint Kinase 2, Oocytes, Ovarian Follicle, Antineoplastic Agents, Ovary

JAX Source

Sci Adv. 2023;9(42):eadg0898.

ISSN

2375-2548

PMID

37862420

DOI

https://doi.org/10.1126/sciadv.adg0898

Grant

This work was supported by V Scholar Award V2017-019 and Jackson Laboratory start-up funds to E.B.-F.

Abstract

Cancer treatments can damage the ovarian follicle reserve, leading to primary ovarian insufficiency and infertility among survivors. Checkpoint kinase 2 (CHEK2) deficiency prevents elimination of oocytes in primordial follicles in female mice exposed to radiation and preserves their ovarian function and fertility. Here, we demonstrate that CHEK2 also coordinates the elimination of oocytes after exposure to standard-of-care chemotherapy drugs. CHEK2 activates two downstream targets-TAp63 and p53-which direct oocyte elimination. CHEK2 knockout or pharmacological inhibition preserved ovarian follicle reserve after radiation and chemotherapy. However, the lack of specificity for CHEK2 among available inhibitors limits their potential for clinical development. These findings demonstrate that CHEK2 is a master regulator of the ovarian cellular response to damage caused by radiation and chemotherapy and warrant the development of selective inhibitors specific to CHEK2 as a potential avenue for ovario-protective treatments.

Comments

Copyright © 2023 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).

Download

Share

COinS