REGULATION OF THE ACTIVITY OF TAp63α IN OOCYTES BY ITS OLIGOMERIC STATE

TAp63α was shown to be a key player in the cellular response to DNA damage in oocytes. γ-irradiation induced DNA double strand breaks lead to the activation of p63 by phosphorylation which in turn results in the destruction of the damaged germ cell. Remarkably, compared to its famous homologue p53 in somatic cells, TAp63α is already highly expressed in undamaged oocytes, suggesting that its activity is under tight control of an inhibitory mechanism. However, the structural mechanism by which TAp63α is inhibited was so far unknown. Here we show that TAp63α is kept in an inactive dimeric state in vitro and in vivo. Disruption of an inhibitory interaction network involving the N- and C-terminus of the protein leads to the formation of active tetramers which show an approximately 20 fold higher affinity to DNA. Tetramerization seems to be an irreversible step since dephosphorylation of the in vivo activated protein does not restore the inactive dimeric state. Furthermore, we show that a recently identified helix in the central tetramerization domain of p63 is essential for the formation of stable tetramers and seems to compete with the N-terminal transactivation domain for the same binding site on the tetramerization domain. Our results demonstrate how TAp63α is inhibited by complex domain-domain-interactions and provide the basis for understanding the delicate mechanism of how females ensure genetic stability of their finite number of oocytes.