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. © 2013 Halaby et al.