Mechanisms of chemotherapy-induced oocyte death through activation of TAp63α

in Reproduction
Authors:
Niklas Gutfreund Institute of Biophysical Chemistry and Center for Biomolecular Magnetic Resonance, Goethe University, Frankfurt/Main, Germany

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Marcel Tuppi Institute of Biophysical Chemistry and Center for Biomolecular Magnetic Resonance, Goethe University, Frankfurt/Main, Germany

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Birgit Schäfer Institute of Biophysical Chemistry and Center for Biomolecular Magnetic Resonance, Goethe University, Frankfurt/Main, Germany

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Francesca Gioia Klinger Saint Camillus International University of Health Sciences, Faculty Department, Rome, Italy

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Anja Kirchhof Institute of Biochemistry II, Faculty of Medicine, Goethe University Frankfurt, Frankfurt, Germany

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Antonia Hofmann Institute of Biochemistry II, Faculty of Medicine, Goethe University Frankfurt, Frankfurt, Germany

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Ivan Dikic Institute of Biochemistry II, Faculty of Medicine, Goethe University Frankfurt, Frankfurt, Germany
Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, Frankfurt, Germany
Max Planck Institute of Biophysics, Frankfurt, Germany

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Volker Dötsch Institute of Biophysical Chemistry and Center for Biomolecular Magnetic Resonance, Goethe University, Frankfurt/Main, Germany

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https://orcid.org/0000-0001-5720-212X

Correspondence should be addressed to V Dötsch: vdoetsch@em.uni-frankfurt.de
DOI:
https://doi.org/10.1530/REP-24-0225
Volume/Issue:
Volume 169: Issue 5
Article ID:
e240225
Article Type:
Research Article
Online Publication Date:
28 Apr 2025
Copyright:
© the author(s) 2025
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In brief

Induction of DNA double-strand breaks results in oocyte death caused by the activation of TAp63α. This study investigates which chemotherapeutic drugs activate p63 and which cause oocyte death without p63 activation.

Abstract

Primary ovarian insufficiency is a severe side effect of classical chemotherapy and radiotherapy in treatment of female cancer patients of reproductive age. The p53-homolog TAp63α emerged as the key protein regulating apoptosis following DNA damage in oocytes of primordial follicles. In this study, we monitored the toxicity of widely used chemotherapeutic agents on oocytes of primordial follicles utilizing a GFP-c-kit transgenic mouse model, the involvement of active TAp63α and the mechanism of action leading to its activation. Our studies show that alkylating agents and topoisomerase II poisons are potent activators of TAp63α by directly inducing DNA damage. Oxidative stress and DNA intercalation were not sufficient to trigger TAp63α activation despite showing a strong general toxicity. These results are in agreement with several previous investigations that have demonstrated that DNA double-strand breaks are the most effective way to initiate apoptosis in oocytes of primordial follicles. The widely used catalytic topoisomerase II inhibitor ICRF-187 was able to prevent activation of TAp63α by the topoisomerase II poison doxorubicin but did not prevent oocyte death, suggesting an alternative mechanism of cell death induction.

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Print ISSN:
1470-1626
Online ISSN:
1741-7899

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