title: Synergistic interaction of Rnf8 and p53 in the protection against genomic instability and tumorigenesis.
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.
authors: Department of Medical Biophysics, University of Toronto and Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada.
authors: Marie-Jo
authors: MJ
authors: Halaby
authors: Anne
authors: A
authors: Hakem
authors: Li
authors: L
authors: Li
authors: Samah
authors: S
authors: El Ghamrasni
authors: Shriram
authors: S
authors: Venkatesan
authors: Prakash M
authors: PM
authors: Hande
authors: Otto
authors: O
authors: Sanchez
authors: Razqallah
authors: R
authors: Hakem
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D042002:Chromatin Assembly and Disassembly / Q000235:genetics; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage; D004260:DNA Repair / Q000235:genetics; D005347:Fibroblasts / Q000166:cytology; D042822:Genomic Instability; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism
chemical_list: D016159:Tumor Suppressor Protein p53; C549817:Rnf8 protein, mouse; D044767:Ubiquitin-Protein Ligases
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