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DNA damage in oocytes induces a switch of the quality control factor TAp63α from dimer to tetramer

  • TAp63a, 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 TAp63a’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 TAp63a inhibition remains unknown. Here, we show that TAp63a 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 TAp63a 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 TAp63a is inhibited by complex domain-domain interactions that provide the basis for regulating quality control in oocytes.

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Author:Gregor Deutsch, Elisabeth M. Zielonka, Daniel Coutandin, Tobias Alexander WeberGND, Birgit Schäfer, Jens Hannewald, Laura Martina Luh, Florian Durst, Mohamed Ibrahim, Jan HoffmannORCiDGND, Frank H. Niesen, Aycan Sentürk, Hana Kunkel, Bernd BrutschyGND, Enrico SchleiffORCiDGND, Stefan KnappORCiD, Amparo Acker-PalmerORCiDGND, Manuel GrezGND, Frank McKeon, Volker DötschORCiDGND
URN:urn:nbn:de:hebis:30:3-369328
URL:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3087504
DOI:https://doi.org/10.1016/j.cell.2011.01.013
ISSN:0092-8674
ISSN:1097-4172
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/21335238
Parent Title (English):Cell
Publisher:Cell Press
Place of publication:Cambridge, Mass
Document Type:Article
Language:English
Date of Publication (online):2015/02/10
Year of first Publication:2011
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2015/02/10
Volume:144
Issue:4
Page Number:11
First Page:566
Last Page:576
Note:
Open access under CC BY license.
HeBIS-PPN:36824279X
Institutes:Biochemie, Chemie und Pharmazie / Biochemie und Chemie
Biowissenschaften / Biowissenschaften
Angeschlossene und kooperierende Institutionen / Georg-Speyer-Haus
Exzellenzcluster / Exzellenzcluster Makromolekulare Komplexe
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie
Sammlungen:Universitätspublikationen
Sammlung Biologie / Sondersammelgebiets-Volltexte
Licence (German):License LogoCreative Commons - Namensnennung 3.0