Loss of PUMA protects the ovarian reserve during DNA-damaging chemotherapy and preserves fertility
AuthorQuynh-Nhu, N; Zerafa, N; Liew, SH; Morgan, FH; Strasser, A; Scott, CL; Findlay, JK; Hickey, M; Hutt, KJ
Source TitleCell Death and Disease
PublisherNATURE PUBLISHING GROUP
University of Melbourne Author/sFindlay, John; Scott, Clare; Hickey, Martha; Strasser, Andreas; Nguyen, Quynh-Nhu
AffiliationObstetrics and Gynaecology
Medical Biology (W.E.H.I.)
Document TypeJournal Article
CitationsQuynh-Nhu, N., Zerafa, N., Liew, S. H., Morgan, F. H., Strasser, A., Scott, C. L., Findlay, J. K., Hickey, M. & Hutt, K. J. (2018). Loss of PUMA protects the ovarian reserve during DNA-damaging chemotherapy and preserves fertility. CELL DEATH & DISEASE, 9 (6), https://doi.org/10.1038/s41419-018-0633-7.
Access StatusOpen Access
Female gametes are stored in the ovary in structures called primordial follicles, the supply of which is non-renewable. It is well established that DNA-damaging cancer treatments can deplete the ovarian reserve of primordial follicles, causing premature ovarian failure and infertility. The precise mechanisms underlying this chemotherapy-driven follicle loss are unclear, and this has limited the development of targeted ovarian-protective agents. To address this fundamental knowledge gap, we used gene deletion mouse models to examine the role of the DNA damage-induced pro-apoptotic protein, PUMA, and its transcriptional activator TAp63, in primordial follicle depletion caused by treatment with cyclophosphamide or cisplatin. Cyclophosphamide caused almost complete destruction of the primordial follicle pool in adult wild-type (WT) mice, and a significant destructive effect was also observed for cisplatin. In striking contrast, Puma-/- mice retained 100% of their primordial follicles following either genotoxic treatment. Furthermore, elimination of PUMA alone completely preserved fertility in cyclophosphamide-treated mice, indicating that oocytes rescued from DNA damage-induced death can repair themselves sufficiently to support reproductive function and offspring health. Primordial follicles were also protected in TAp63-/- mice following cisplatin treatment, but not cyclophosphamide, suggesting mechanistic differences in the induction of apoptosis and depletion of the ovarian reserve in response to these different chemotherapies. These studies identify PUMA as a crucial effector of apoptosis responsible for depletion of primordial follicles following exposure to cyclophosphamide or cisplatin, and this indicates that inhibition of PUMA may be an effective ovarian-protective strategy during cancer treatment in women.
- Click on "Export Reference in RIS Format" and choose "open with... Endnote".
- Click on "Export Reference in RIS Format". Login to Refworks, go to References => Import References