Oocyte DNA damage quality control requires consecutive interplay of CHK2 and CK1 to activate p63
| Autor: | Laura M. Luh, Florian R. Greten, Christian Behrends, Francesca Gioia Klinger, Sebastian Kehrloesser, Massimo De Felici, Stefan Knapp, Valerio Rossi, Alexander Strubel, Katharina Hötte, Ernst H. K. Stelzer, D. Coutandin, Marcel Tuppi, Birgit Schäfer, Volker Dötsch, Tiago De Oliveira, Meike Hoffmeister |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
DNA damage Biology Premature ovarian insufficiency 03 medical and health sciences Mice Structural Biology Cell Line Tumor medicine Animals Humans Settore BIO/10 Phosphorylation Molecular Biology Settore BIO/17 Settore BIO/11 Kinase Casein Kinase I Tumor Suppressor Proteins Settore BIO/13 Oocyte Cell biology Checkpoint Kinase 2 030104 developmental biology medicine.anatomical_structure Apoptosis Doxorubicin Oocytes Casein kinase 1 Folliculogenesis Cisplatin Protein Multimerization DNA Damage Transcription Factors |
| Zdroj: | Nature structuralmolecular biology. 25(3) |
| ISSN: | 1545-9985 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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