title: Quality control in oocytes by p63 is based on a spring-loaded activation mechanism on the molecular and cellular level.
abstract: Mammalian oocytes are arrested in the dictyate stage of meiotic prophase I for long periods of time, during which the high concentration of the p53 family member TAp63α sensitizes them to DNA damage-induced apoptosis. TAp63α is kept in an inactive and exclusively dimeric state but undergoes rapid phosphorylation-induced tetramerization and concomitant activation upon detection of DNA damage. Here we show that the TAp63α dimer is a kinetically trapped state. Activation follows a spring-loaded mechanism not requiring further translation of other cellular factors in oocytes and is associated with unfolding of the inhibitory structure that blocks the tetramerization interface. Using a combination of biophysical methods as well as cell and ovary culture experiments we explain how TAp63α is kept inactive in the absence of DNA damage but causes rapid oocyte elimination in response to a few DNA double strand breaks thereby acting as the key quality control factor in maternal reproduction.
authors.affiliation: Institute of Biophysical Chemistry, Goethe University, Frankfurt, Germany.|Center for Biomolecular Magnetic Resonance, Goethe University, Frankfurt, Germany.|Cluster of Excellence Macromolecular Complexes, Goethe University, Frankfurt, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Coutandin
authors.affiliation: Institute of Biophysical Chemistry, Goethe University, Frankfurt, Germany.|Center for Biomolecular Magnetic Resonance, Goethe University, Frankfurt, Germany.|Cluster of Excellence Macromolecular Complexes, Goethe University, Frankfurt, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Osterburg
authors.affiliation: Institute of Biophysical Chemistry, Goethe University, Frankfurt, Germany.|Center for Biomolecular Magnetic Resonance, Goethe University, Frankfurt, Germany.|Cluster of Excellence Macromolecular Complexes, Goethe University, Frankfurt, Germany.
authors.forename: Ratnesh Kumar
authors.initials: RK
authors.lastname: Srivastav
authors.affiliation: Institute of Biophysical Chemistry, Goethe University, Frankfurt, Germany.|Center for Biomolecular Magnetic Resonance, Goethe University, Frankfurt, Germany.|Cluster of Excellence Macromolecular Complexes, Goethe University, Frankfurt, Germany.
authors.forename: Manuela
authors.initials: M
authors.lastname: Sumyk
authors.affiliation: Institute of Biophysical Chemistry, Goethe University, Frankfurt, Germany.|Center for Biomolecular Magnetic Resonance, Goethe University, Frankfurt, Germany.|Cluster of Excellence Macromolecular Complexes, Goethe University, Frankfurt, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Kehrloesser
authors.affiliation: Institute of Biophysical Chemistry, Goethe University, Frankfurt, Germany.|Center for Biomolecular Magnetic Resonance, Goethe University, Frankfurt, Germany.|Cluster of Excellence Macromolecular Complexes, Goethe University, Frankfurt, Germany.
authors.forename: Jakob
authors.initials: J
authors.lastname: Gebel
authors.affiliation: Institute of Biophysical Chemistry, Goethe University, Frankfurt, Germany.|Center for Biomolecular Magnetic Resonance, Goethe University, Frankfurt, Germany.|Cluster of Excellence Macromolecular Complexes, Goethe University, Frankfurt, Germany.
authors.forename: Marcel
authors.initials: M
authors.lastname: Tuppi
authors.affiliation: MS-DTB-C Protein Purification, Merck KGaA, Darmstadt, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Hannewald
authors.affiliation: Institute of Biophysical Chemistry, Goethe University, Frankfurt, Germany.|Center for Biomolecular Magnetic Resonance, Goethe University, Frankfurt, Germany.|Cluster of Excellence Macromolecular Complexes, Goethe University, Frankfurt, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Schäfer
authors.affiliation: Nuffield Department of Medicine, Structural Genomics Consortium, University of Oxford, Oxford, United Kingdom.
authors.forename: Eidarus
authors.initials: E
authors.lastname: Salah
authors.affiliation: Nuffield Department of Medicine, Structural Genomics Consortium, University of Oxford, Oxford, United Kingdom.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Mathea
authors.affiliation: Georg-Speyer Haus, Frankfurt, Germany.
authors.forename: Uta
authors.initials: U
authors.lastname: Müller-Kuller
authors.affiliation: ISIS Neutron and Muon Source, Rutherford Appleton Laboratory, Didcot, United Kingdom.
authors.forename: James
authors.initials: J
authors.lastname: Doutch
authors.affiliation: Georg-Speyer Haus, Frankfurt, Germany.
authors.forename: Manuel
authors.initials: M
authors.lastname: Grez
authors.affiliation: Nuffield Department of Medicine, Structural Genomics Consortium, University of Oxford, Oxford, United Kingdom.|Institute for Pharmaceutical Chemistry, Goethe University, Frankfurt, Germany.|Buchmann Institute for Molecular Life Science, Goethe University, Frankfurt, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Knapp
authors.affiliation: Institute of Biophysical Chemistry, Goethe University, Frankfurt, Germany.|Center for Biomolecular Magnetic Resonance, Goethe University, Frankfurt, Germany.|Cluster of Excellence Macromolecular Complexes, Goethe University, Frankfurt, Germany.
authors.forename: Volker
authors.identifier: 0000-0001-5720-212X
authors.initials: V
authors.lastname: Dötsch
mesh_terms: D000818:Animals; D017209:Apoptosis; D004249:DNA Damage; D005260:Female; D051379:Mice; D009865:Oocytes / Q000502:physiology*; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D055503:Protein Multimerization; D011499:Protein Processing, Post-Translational; D011786:Quality Control; D015534:Trans-Activators / Q000378:metabolism*
chemical_list: D010750:Phosphoproteins; D015534:Trans-Activators; C486419:Trp63 protein, mouse
keywords: DNA damage; E. coli; biophysics; cell biology; kinetically trapped state; mouse; oocytes; p63; quality control; spring-loaded activation; structural biology