Synergistic Interaction of Rnf8 and p53 in the Protection against Genomic Instability and Tumorigenesis |
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Authors: | Marie-Jo Halaby Anne Hakem Li Li Samah El Ghamrasni Shriram Venkatesan Prakash M. Hande Otto Sanchez Razqallah Hakem |
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Affiliation: | 1.Department of Medical Biophysics, University of Toronto and Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada;2.Department of Physiology, Yong Loo Lin School of Medicine and Tembusu College, National University of Singapore, Singapore, Singapore;3.University of Ontario Institute of Technology, Oshawa, Ontario, Canada;Cincinnati Children''s Hospital Medical Center, United States of America |
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Abstract: | Rnf8 is an E3 ubiquitin ligase that plays a key role in the DNA damage response as well as in the maintenance of telomeres and chromatin remodeling. Rnf8−/− mice exhibit developmental defects and increased susceptibility to tumorigenesis. We observed that levels of p53, a central regulator of the cellular response to DNA damage, increased in Rnf8−/− mice in a tissue- and cell type–specific manner. To investigate the role of the p53-pathway inactivation on the phenotype observed in Rnf8−/− mice, we have generated Rnf8−/−p53−/− mice. Double-knockout mice showed similar growth retardation defects and impaired class switch recombination compared to Rnf8−/− mice. In contrast, loss of p53 fully rescued the increased apoptosis and reduced number of thymocytes and splenocytes in Rnf8−/− mice. Similarly, the senescence phenotype of Rnf8−/− mouse embryonic fibroblasts was rescued in p53 null background. Rnf8−/−p53−/− cells displayed defective cell cycle checkpoints and DNA double-strand break repair. In addition, Rnf8−/−p53−/− mice had increased levels of genomic instability and a remarkably elevated tumor incidence compared to either Rnf8−/− or p53−/− mice. Altogether, the data in this study highlight the importance of p53-pathway activation upon loss of Rnf8, suggesting that Rnf8 and p53 functionally interact to protect against genomic instability and tumorigenesis. |
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