Chfr and RNF8 synergistically regulate ATM activation

Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA.
Nature Structural & Molecular Biology (Impact Factor: 13.31). 06/2011; 18(7):761-8. DOI: 10.1038/nsmb.2078
Source: PubMed

ABSTRACT Protein ubiquitination is a crucial component of the DNA damage response. To study the mechanism of the DNA damage-induced ubiquitination pathway, we analyzed the impact of the loss of two E3 ubiquitin ligases, RNF8 and Chfr. Notably, DNA damage-induced activation of ATM kinase is suppressed in cells deficient in both RNF8 and Chfr (double-knockout, or DKO), and DKO mice develop thymic lymphomas that are nearly diploid but harbor clonal chromosome translocations. Moreover, DKO mice and cells are hypersensitive to ionizing radiation. We present evidence that RNF8 and Chfr synergistically regulate histone ubiquitination to control histone H4 Lys16 acetylation through MRG15-dependent acetyltransferase complexes. Through these complexes, RNF8 and Chfr affect chromatin relaxation and modulate ATM activation and DNA damage response pathways. Collectively, our findings demonstrate that two chromatin-remodeling factors, RNF8 and Chfr, function together to activate ATM and maintain genomic stability in vivo.

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    • "CHFR ubiquitinates and negatively regulates histone deacetylase 1 (HDAC1), promoting p21 gene expression to induce p21-dependent cell cycle arrest [19]. It also synergistically maintains genomic stability with another E3 ubiquitin ligase, ring finger protein 8 (RNF8), and inhibits tumorigenesis by modulation of histone modifications and suppression of ataxia telangiectasia mutated (ATM) kinase activation [25]. CHFR and RNF8 double-knockout mice showed low H2A and H2B ubiquitination , H4K16 acetylation in thymocytes and suppressed ATM activation in response to DNA damage response, thereby causing T-cell lymphoma to develop. "
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