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.
Highlights
The p53 protein family with its three members p53, p63 and p73 plays very important roles in the surveillance of genetic and cellular stability (Levine et al, 2011)
TAp63a contains three folded domains, the DNA binding domain (DBD), the tetramerization domain (TD) and the SAM domain that are linked by unstructured regions
We have shown that the open state can be detected by a conformation sensitive pull-down experiment: tetrameric mutants with an intact transactivation domain (TAD) can be pulled down with a GST-transactivation inhibitory domain (TID) construct (569–616) (Straub et al, 2010)
Summary
The p53 protein family with its three members p53, p63 and p73 plays very important roles in the surveillance of genetic and cellular stability (Levine et al, 2011). The most ancient function of this family is the maintenance of genetic quality in germ cells since even short lived eukaryotic animals express a p63-like protein in their germ cells (Ollmann et al, 2000; Derry et al, 2001; Brodsky et al, 2000; Suh et al, 2006; Ou et al, 2007). Up to 10 diverse p63 isoforms exist with the longest one, TAp63a, being highly expressed in primary oocytes that are arrested in prophase of meiosis I.
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