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PLoS Genet. 2013;9(1):e1003259. doi: 10.1371/journal.pgen.1003259. Epub 2013 Jan 31.

Synergistic interaction of Rnf8 and p53 in the protection against genomic instability and tumorigenesis.

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Department of Medical Biophysics, University of Toronto and Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada.


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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