DNA Damage in Oocytes Induces a Switch of the Quality Control Factor TAp63α from Dimer to Tetramer
| Autor: | Stefan Knapp, Gregor B. Deutsch, Hana Kunkel, Frank McKeon, Elisabeth M. Zielonka, Amparo Acker-Palmer, Birgit Schäfer, Frank H. Niesen, Jens Hannewald, Laura M. Luh, D. Coutandin, Jan Hoffmann, Tobias Alexander Weber, Volker Dötsch, Aycan Sentürk, Florian Durst, Manuel Grez, Mohamed Ibrahim, Bernd Brutschy, Enrico Schleiff |
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| Rok vydání: | 2011 |
| Předmět: |
Models
Molecular DNA damage Biology Article General Biochemistry Genetics and Molecular Biology Dephosphorylation Mice 03 medical and health sciences chemistry.chemical_compound Transactivation 0302 clinical medicine Tetramer ddc:570 Animals Phosphorylation Binding site 030304 developmental biology 0303 health sciences Biochemistry Genetics and Molecular Biology(all) DNA Phosphoproteins Cell biology Biochemistry chemistry Gamma Rays 030220 oncology & carcinogenesis Oocytes Trans-Activators Female Protein Multimerization Tumor Suppressor Protein p53 Dimerization Alpha helix |
| Zdroj: | Cell |
| ISSN: | 0092-8674 |
| DOI: | 10.1016/j.cell.2011.01.013 |
| Popis: | Summary TAp63α, a homolog of the p53 tumor suppressor, is a quality control factor in the female germline. Remarkably, already undamaged oocytes express high levels of the protein, suggesting that TAp63α's activity is under tight control of an inhibitory mechanism. Biochemical studies have proposed that inhibition requires the C-terminal transactivation inhibitory domain. However, the structural mechanism of TAp63α inhibition remains unknown. Here, we show that TAp63α is kept in an inactive dimeric state. We reveal that relief of inhibition leads to tetramer formation with ∼20-fold higher DNA affinity. In vivo, phosphorylation-triggered tetramerization of TAp63α is not reversible by dephosphorylation. Furthermore, we show that a helix in the oligomerization domain of p63 is crucial for tetramer stabilization and competes with the transactivation domain for the same binding site. Our results demonstrate how TAp63α is inhibited by complex domain-domain interactions that provide the basis for regulating quality control in oocytes. Graphical Abstract Highlights ► TAp63α is inhibited in a dimeric state by complex domain-domain interactions ► Phosphorylation-triggered TAp63α activation upon DNA damage requires tetramerization ► Tetramer stabilization requires the second helix H2 of the tetramerization domain ► Tetramerization domain binding by the transactivation domain is competed by helix H2 |
| Databáze: | OpenAIRE |
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