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Chfr and RNF8 synergistically regulate ATM activation.

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.

Pubmed ID: 21706008 RIS Download

Mesh terms: Acetylation | Animals | Ataxia Telangiectasia Mutated Proteins | Cell Cycle Proteins | Cells, Cultured | Chromatin Assembly and Disassembly | Chromosomal Proteins, Non-Histone | Chromosome Aberrations | DNA Damage | DNA Repair | DNA-Binding Proteins | Enzyme Activation | Genomic Instability | Histones | Lymphoma, T-Cell | Mice | Mice, Knockout | Protein-Serine-Threonine Kinases | Radiation, Ionizing | Trans-Activators | Tumor Suppressor Proteins | Ubiquitin-Protein Ligases | Ubiquitination

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Associated grants

  • Agency: NCI NIH HHS, Id: R01 CA132755-04
  • Agency: NCI NIH HHS, Id: R01 CA130899-04
  • Agency: NCI NIH HHS, Id: R01 CA132755
  • Agency: NCI NIH HHS, Id: CA130899
  • Agency: NCI NIH HHS, Id: CA132755
  • Agency: NCI NIH HHS, Id: R01 CA130899

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