Loss of PUMA protects the ovarian reserve during DNA-damaging chemotherapy and preserves fertility

Quynh Nhu Nguyen, Nadeen Zerafa, Seng H. Liew, F. Hamish Morgan, Andreas Strasser, Clare L. Scott, Jock K. Findlay, Martha Hickey, Karla J. Hutt

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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.

Original languageEnglish
Article number633
Number of pages12
JournalCell Death and Disease
Volume9
Issue number6
DOIs
Publication statusPublished - 1 Jun 2018

Cite this

Nguyen, Quynh Nhu ; Zerafa, Nadeen ; Liew, Seng H. ; Morgan, F. Hamish ; Strasser, Andreas ; Scott, Clare L. ; Findlay, Jock K. ; Hickey, Martha ; Hutt, Karla J. / Loss of PUMA protects the ovarian reserve during DNA-damaging chemotherapy and preserves fertility. In: Cell Death and Disease. 2018 ; Vol. 9, No. 6.
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abstract = "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.",
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Loss of PUMA protects the ovarian reserve during DNA-damaging chemotherapy and preserves fertility. / Nguyen, Quynh Nhu; Zerafa, Nadeen; Liew, Seng H.; Morgan, F. Hamish; Strasser, Andreas; Scott, Clare L.; Findlay, Jock K.; Hickey, Martha; Hutt, Karla J.

In: Cell Death and Disease, Vol. 9, No. 6, 633, 01.06.2018.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Loss of PUMA protects the ovarian reserve during DNA-damaging chemotherapy and preserves fertility

AU - Nguyen, Quynh Nhu

AU - Zerafa, Nadeen

AU - Liew, Seng H.

AU - Morgan, F. Hamish

AU - Strasser, Andreas

AU - Scott, Clare L.

AU - Findlay, Jock K.

AU - Hickey, Martha

AU - Hutt, Karla J.

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