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Nat Struct Mol Biol. 2018 Mar;25(3):261-269. doi: 10.1038/s41594-018-0035-7. Epub 2018 Feb 26.

Oocyte DNA damage quality control requires consecutive interplay of CHK2 and CK1 to activate p63.

Author information

1
Institute of Biophysical Chemistry and Center for Biomolecular Magnetic Resonance and Cluster of Excellence Macromolecular Complexes (CEF), Goethe University, Frankfurt, Germany.
2
Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy.
3
Physical Biology/Physikalische Biologie (IZN, FB 15), Buchmann Institute for Molecular Life Sciences (BMLS), Goethe University, Frankfurt, Germany.
4
Institute of Biochemistry, Brandenburg Medical School (MHB) Theodor Fontane, Neuruppin and Brandenburg an der Havel, Germany.
5
Georg-Speyer-Haus, Institute for Biomedical Research, Frankfurt, Germany.
6
German Cancer Network (DKTK), Frankfurt, Germany.
7
Nuffield Department of Medicine, Structural Genomics Consortium, Oxford University, Oxford, UK.
8
Institute of Pharmaceutical Chemistry, Goethe University, Frankfurt, Germany.
9
Munich Cluster for Systems Neurology, Ludwig-Maximilians-University, Munich, Germany.
10
Institute of Biophysical Chemistry and Center for Biomolecular Magnetic Resonance and Cluster of Excellence Macromolecular Complexes (CEF), Goethe University, Frankfurt, Germany. vdoetsch@em.uni-frankfurt.de.

Abstract

The survival rate of cancer patients is steadily increasing, owing to more efficient therapies. Understanding the molecular mechanisms of chemotherapy-induced premature ovarian insufficiency (POI) could identify targets for prevention of POI. Loss of the primordial follicle reserve is the most important cause of POI, with the p53 family member p63 being responsible for DNA-damage-induced apoptosis of resting oocytes. Here, we provide the first detailed mechanistic insight into the activation of p63, a process that requires phosphorylation by both the priming kinase CHK2 and the executioner kinase CK1 in mouse primordial follicles. We further describe the structural changes induced by phosphorylation that enable p63 to adopt its active tetrameric conformation and demonstrate that previously discussed phosphorylation by c-Abl is not involved in this process. Inhibition of CK1 rescues primary oocytes from doxorubicin and cisplatin-induced apoptosis, thus uncovering a new target for the development of fertoprotective therapies.

PMID:
29483652
DOI:
10.1038/s41594-018-0035-7
[Indexed for MEDLINE]

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