期刊
NATURE STRUCTURAL & MOLECULAR BIOLOGY
卷 25, 期 3, 页码 261-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41594-018-0035-7
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资金
- DFG [DO 545/8-1]
- Centre for Biomolecular Magnetic Resonance (BMRZ)
- Cluster of Excellence Frankfurt (Macromolecular Complexes)
- Funds of the Chemical Industry
- Boehringer Ingelheim
- Covert Italia S.p.A.
- Canadian Institutes for Health Research [1097737]
- Canadian Foundation for Innovation
- Genome Canada through the Ontario Genomics Institute
- GlaxoSmithKline
- Karolinska Institutet
- Knut and Alice Wallenberg Foundation
- Ontario Innovation Trust
- Ontario Ministry for Research and Innovation
- Merck Co., Inc.
- Novartis Research Foundation
- Swedish Agency for Innovation Systems
- Swedish Foundation for Strategic Research
- Wellcome Trust
The survival rate of cancer patients is steadily increasing, owing to more efficient therapies. Understanding the molecular mechanisms of chemotherapy-induced premature ovarian insufficiency (P01) could identify targets for prevention of P01. 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.
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