Meiosis in the female germ line of mammals is distinguished by a prolonged arrest in prophase of meiosis I between homologous chromosome recombination and ovulation1. How DNA damage is detected in these arrested oocytes is poorly understood, but it is variably thought to involve p53, a central tumour suppressor in mammals2,3,4. While the function of p53 in monitoring the genome of somatic cells is clear, a consensus for the importance of p53 for germ line integrity has yet to emerge. Here we show that the p53 homologue p63 (refs 5, 6), and specifically the TAp63 isoform, is constitutively expressed in female germ cells during meiotic arrest and is essential in a process of DNA damage-induced oocyte death not involving p53. We also show that DNA damage induces both the phosphorylation of p63 and its binding to p53 cognate DNA sites and that these events are linked to oocyte death. Our data support a model whereby p63 is the primordial member of the p53 family and acts in a conserved process of monitoring the integrity of the female germ line, whereas the functions of p53 are restricted to vertebrate somatic cells for tumour suppression. These findings have implications for understanding female germ line fidelity, the regulation of fertility and the evolution of tumour suppressor mechanisms.
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We thank R. Schultz, B. Spyropoulos, P. Moens and M. De Luca for gifts of antibodies; A. Lee, G. Perez, C. Morton and Y. Lee for advice and assistance with technical procedures; and V. Doetsch, M. Senoo, F. Pinto, H. Green, A. Sharpe and M. Colaiacova for discussions. A.Y. was supported by a fellowship from the Department of Defence Program in Breast Cancer. This work was supported by grants from the NCI and the NIH to C.P.C. and F.M. Author Contributions E.K.S. established the ovary experimental system, performed the DNA damage experiments with the wild-type, p53-null, and p63-null mice in vivo and in vitro, identified the TAp63 phosphorylation-dependent mobility shift and performed the kinetics linking it to oocyte death. A.Y. generated the anti-TAp63 monoclonal antibodies, designed the TAp63 targeting and genotyping strategies and assisted in the generation of the TAp63 knockout mice. A.K. generated the TAp63 knockout mice and performed the DNA damage experiments on these strains. C.B. performed the TAp63 DNA binding experiments and statistical analyses of data presented in this paper. A.M. generated and characterized the anti-TAp63 antibodies with A.Y. Z.Z. and A.K. performed the bioinformatics analysis of the p53 gene family. J.E. made early contributions on TAp63 expression in human oocytes. R.B. supervised the histopathology analysis. C.C. and F.M. directed the project, and F.M. wrote the manuscript with help from A.Y., A.K. and E.K.S.
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Nature Structural & Molecular Biology (2018)