Quality control in oocytes by p63 is based on a spring-loaded activation mechanism
April 2016. The p53 protein family with its three members p53, p63 and p73 plays very important roles in the surveillance of genetic and cellular stability. Probably 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. In mammals, up to ten different isoforms of p63 exist. The longest isoform, TAp63α, is highly expressed in primary oocytes that are arrested in prophase of meiosis I. Oocytes are kept in this arrest phase until they are needed for ovulation, a period that can take decades in humans. Once oocytes reenter the cell cycle, expression of TAp63α is lost. Since p63 can initiate programmed cell death (apoptosis) the high expression level of TAp63α in oocytes necessitates that its activity is very carefully regulated. To understand the mechanism of inhibition and activation a team of scientists led by Volker Dötsch from the Goethe University Frankfurt started to characterize the structural requirements for the formation of the closed and dimeric state of TAp63α. Using a combination of biophysical methods as well as cell and ovary culture experiments the team was able to 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. It thereby acts as the key quality control factor in maternal reproduction. The team showed that the inhibited conformation is a kinetically trapped state and that the oocyte contains all factors necessary to activate p63 without requirement of further protein expression. TAp63α is kept in an inactive and exclusively dimeric state but undergoes rapid phosphorylation-induced tetramerization and concomitant activation upon detection of DNA damage. The data demonstrate that activation of TAp63α follows a spring-loaded mechanism and explains why oocytes are far more sensitive to DNA damage than the surrounding follicular cells. More...
Institute of Biophysical Chemistry
Goethe University Frankfurt