1. Structural Biology and Molecular Biophysics
  2. Cell Biology
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Quality control in oocytes by p63 is based on a spring-loaded activation mechanism on the molecular and cellular level

  1. Daniel Coutandin
  2. Christian Osterburg
  3. Ratnesh Kumar Srivastav
  4. Manuela Sumyk
  5. Sebastian Kehrloesser
  6. Jakob Gebel
  7. Marcel Tuppi
  8. Jens Hannewald
  9. Birgit Schäfer
  10. Eidarus Salah
  11. Sebastian Mathea
  12. Uta Müller-Kuller
  13. James Doutch
  14. Manuel Grez
  15. Stefan Knapp
  16. Volker Dötsch  Is a corresponding author
  1. Goethe University, Germany
  2. Merck KGaA, Germany
  3. University of Oxford, United Kingdom
  4. Georg-Speyer Haus, Germany
  5. ISIS Neutron and Muon Source, United Kingdom
  6. Georg-Speyer-Haus, Germany
Research Article
  • Cited 30
  • Views 1,856
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Cite this article as: eLife 2016;5:e13909 doi: 10.7554/eLife.13909

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.

Article and author information

Author details

  1. Daniel Coutandin

    Institute of Biophysical Chemistry and Center for Biomolecular Magnetic Resonance and Cluster of Excellence Macromolecular Complexes, Goethe University, Frankfurt, Germany
    Competing interests
    No competing interests declared.
  2. Christian Osterburg

    Institute of Biophysical Chemistry and Center for Biomolecular Magnetic Resonance and Cluster of Excellence Macromolecular Complexes, Goethe University, Frankfurt, Germany
    Competing interests
    No competing interests declared.
  3. Ratnesh Kumar Srivastav

    Institute of Biophysical Chemistry and Center for Biomolecular Magnetic Resonance and Cluster of Excellence Macromolecular Complexes, Goethe University, Frankfurt, Germany
    Competing interests
    No competing interests declared.
  4. Manuela Sumyk

    Institute of Biophysical Chemistry and Center for Biomolecular Magnetic Resonance and Cluster of Excellence Macromolecular Complexes, Goethe University, Frankfurt, Germany
    Competing interests
    No competing interests declared.
  5. Sebastian Kehrloesser

    Institute of Biophysical Chemistry and Center for Biomolecular Magnetic Resonance and Cluster of Excellence Macromolecular Complexes, Goethe University, Frankfurt, Germany
    Competing interests
    No competing interests declared.
  6. Jakob Gebel

    Institute of Biophysical Chemistry and Center for Biomolecular Magnetic Resonance and Cluster of Excellence Macromolecular Complexes, Goethe University, Frankfurt, Germany
    Competing interests
    No competing interests declared.
  7. Marcel Tuppi

    Institute of Biophysical Chemistry and Center for Biomolecular Magnetic Resonance and Cluster of Excellence Macromolecular Complexes, Goethe University, Frankfurt, Germany
    Competing interests
    No competing interests declared.
  8. Jens Hannewald

    MS-DTB-C Protein Purification, Merck KGaA, Darmstadt, Germany
    Competing interests
    No competing interests declared.
  9. Birgit Schäfer

    Institute of Biophysical Chemistry and Center for Biomolecular Magnetic Resonance and Cluster of Excellence Macromolecular Complexes, Goethe University, Frankfurt, Germany
    Competing interests
    No competing interests declared.
  10. Eidarus Salah

    Nuffield Department of Medicine, Structural Genomics Consortium, University of Oxford, Oxford, United Kingdom
    Competing interests
    No competing interests declared.
  11. Sebastian Mathea

    Nuffield Department of Medicine, Structural Genomics Consortium, University of Oxford, Oxford, United Kingdom
    Competing interests
    No competing interests declared.
  12. Uta Müller-Kuller

    Georg-Speyer Haus, Frankfurt, Germany
    Competing interests
    No competing interests declared.
  13. James Doutch

    Rutherford Appleton Laboratory, ISIS Neutron and Muon Source, Dodcot, United Kingdom
    Competing interests
    No competing interests declared.
  14. Manuel Grez

    Georg-Speyer-Haus, Frankfurt, Germany
    Competing interests
    No competing interests declared.
  15. Stefan Knapp

    Nuffield Department of Medicine, Structural Genomics Consortium, University of Oxford, Oxford, United Kingdom
    Competing interests
    No competing interests declared.
  16. Volker Dötsch

    Institute of Biophysical Chemistry and Center for Biomolecular Magnetic Resonance and Cluster of Excellence Macromolecular Complexes, Goethe University, Frankfurt, Germany
    For correspondence
    vdoetsch@em.uni-frankfurt.de
    Competing interests
    Volker Dötsch, Reviewing editor, eLife.

Ethics

Animal experimentation: The work with mice was conducted according to the regulations of the Goethe University and the DFG (according to {section sign} 4 TierSchG) and supervised by the Tierschutzbeauftragte of Goethe University.

Reviewing Editor

  1. Joaquín M Espinosa, University of Colorado Denver School of Medicine, United States

Publication history

  1. Received: December 18, 2015
  2. Accepted: March 28, 2016
  3. Accepted Manuscript published: March 29, 2016 (version 1)
  4. Version of Record published: April 29, 2016 (version 2)

Copyright

© 2016, Coutandin et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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