title: DNA damage in oocytes induces a switch of the quality control factor TAp63α from dimer to tetramer.
abstract: 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.
authors.affiliation: Institute of Biophysical Chemistry and Center for Biomolecular Magnetic Resonance, Goethe University, Frankfurt, Germany. vdoetsch@em.uni-frankfurt.de
authors.forename: Gregor B
authors.initials: GB
authors.lastname: Deutsch
authors.forename: Elisabeth M
authors.initials: EM
authors.lastname: Zielonka
authors.forename: Daniel
authors.initials: D
authors.lastname: Coutandin
authors.forename: Tobias A
authors.initials: TA
authors.lastname: Weber
authors.forename: Birgit
authors.initials: B
authors.lastname: Schäfer
authors.forename: Jens
authors.initials: J
authors.lastname: Hannewald
authors.forename: Laura M
authors.initials: LM
authors.lastname: Luh
authors.forename: Florian G
authors.initials: FG
authors.lastname: Durst
authors.forename: Mohamed
authors.initials: M
authors.lastname: Ibrahim
authors.forename: Jan
authors.initials: J
authors.lastname: Hoffmann
authors.forename: Frank H
authors.initials: FH
authors.lastname: Niesen
authors.forename: Aycan
authors.initials: A
authors.lastname: Sentürk
authors.forename: Hana
authors.initials: H
authors.lastname: Kunkel
authors.forename: Bernd
authors.initials: B
authors.lastname: Brutschy
authors.forename: Enrico
authors.initials: E
authors.lastname: Schleiff
authors.forename: Stefan
authors.initials: S
authors.lastname: Knapp
authors.forename: Amparo
authors.initials: A
authors.lastname: Acker-Palmer
authors.forename: Manuel
authors.initials: M
authors.lastname: Grez
authors.forename: Frank
authors.initials: F
authors.lastname: McKeon
authors.forename: Volker
authors.initials: V
authors.lastname: Dötsch
mesh_terms: D000818:Animals; D004247:DNA / Q000378:metabolism; D019281:Dimerization; D005260:Female; D005720:Gamma Rays; D051379:Mice; D008958:Models, Molecular; D009865:Oocytes / Q000378:metabolism*; D010750:Phosphoproteins / Q000737:chemistry* / Q000378:metabolism*; D010766:Phosphorylation; D055503:Protein Multimerization; D015534:Trans-Activators / Q000737:chemistry* / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D010750:Phosphoproteins; D015534:Trans-Activators; C486419:Trp63 protein, mouse; D016159:Tumor Suppressor Protein p53; D004247:DNA