Quality control in oocytes by p63 is based on a spring-loaded activation mechanism on the molecular and cellular level
- Goethe University, Germany
- Merck KGaA, Germany
- University of Oxford, United Kingdom
- Georg-Speyer Haus, Germany
- ISIS Neutron and Muon Source, United Kingdom
- Georg-Speyer-Haus, Germany
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.
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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.
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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Quality control in oocytes by p63 is based on a spring-loaded activation mechanism on the molecular and cellular level
eLife 5:e13909.
https://doi.org/10.7554/eLife.13909
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