Quality control in oocytes by p63 is based on a spring-loaded activation mechanism on the molecular and cellular level.
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Authors
Coutandin, Daniel
Osterburg, Christian
Srivastav, Ratnesh Kumar
Sumyk, Manuela
Gebel, Jakob
Tuppi, Marcel
Hannewald, Jens
Schäfer, Birgit
Salah, Eidarus
Mathea, Sebastian
Müller-Kuller, Uta
Doutch, James
Grez, Manuel
Knapp, Stefan
Publication Date
2016-03-14Journal Title
Elife
ISSN
2050-084X
Publisher
eLife Sciences Publications, Ltd
Volume
5
Language
eng
Type
Article
Physical Medium
Electronic
Metadata
Show full item recordCitation
Coutandin, D., Osterburg, C., Srivastav, R. K., Sumyk, M., Kehrloesser, S., Gebel, J., Tuppi, M., et al. (2016). Quality control in oocytes by p63 is based on a spring-loaded activation mechanism on the molecular and cellular level.. Elife, 5 https://doi.org/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.
Keywords
Oocytes, Animals, Mice, DNA Damage, Trans-Activators, Phosphoproteins, Apoptosis, Protein Processing, Post-Translational, Phosphorylation, Quality Control, Female, Protein Multimerization
Identifiers
External DOI: https://doi.org/10.7554/eLife.13909
This record's URL: https://www.repository.cam.ac.uk/handle/1810/285018
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