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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Author details
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
- Joaquín M Espinosa, University of Colorado Denver School of Medicine, United States
Publication history
- Received: December 18, 2015
- Accepted: March 28, 2016
- Accepted Manuscript published: March 29, 2016 (version 1)
- 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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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
Further reading
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- Biochemistry and Chemical Biology
- Structural Biology and Molecular Biophysics
Mitochondrial ATP production in cardiac ventricular myocytes must be continually adjusted to rapidly replenish the ATP consumed by the working heart. Two systems are known to be critical in this regulation: mitochondrial matrix Ca2+ ([Ca2+]m) and blood flow that is tuned by local ventricular myocyte metabolic signaling. However, these two regulatory systems do not fully account for the physiological range of ATP consumption observed. We report here on the identity, location, and signaling cascade of a third regulatory system -- CO2/bicarbonate. CO2 is generated in the mitochondrial matrix as a metabolic waste product of the oxidation of nutrients that powers ATP production. It is a lipid soluble gas that rapidly permeates the inner mitochondrial membrane (IMM) and produces bicarbonate (HCO3-) in a reaction accelerated by carbonic anhydrase (CA). The bicarbonate level is tracked physiologically by a bicarbonate-activated adenylyl cyclase, soluble adenylyl cyclase (sAC). Using structural Airyscan super-resolution imaging and functional measurements we find that sAC is primarily inside the mitochondria of ventricular myocytes where it generates cAMP when activated by HCO3-. Our data strongly suggest that ATP production in these mitochondria is regulated by this cAMP signaling cascade operating within the inter-membrane space (IMS) by activating local EPAC1 (Exchange Protein directly Activated by cAMP) which turns on Rap1 (Ras-related protein 1). Thus, mitochondrial ATP production is shown to be increased by bicarbonate-triggered sAC signaling through Rap1. Additional evidence is presented indicating that the cAMP signaling itself does not occur directly in the matrix. We also show that this third signaling process involving bicarbonate and sAC activates the cardiac mitochondrial ATP production machinery by working independently of, yet in conjunction with, [Ca2+]m-dependent ATP production to meet the energy needs of cellular activity in both health and disease. We propose that the bicarbonate and calcium signaling arms function in a resonant or complementary manner to match mitochondrial ATP production to the full range of energy consumption in cardiac ventricular myocytes in health and disease.
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- Biochemistry and Chemical Biology
- Structural Biology and Molecular Biophysics
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