Chfr and RNF8 synergistically regulate ATM activation

Nat Struct Mol Biol. 2011 Jun 26;18(7):761-8. doi: 10.1038/nsmb.2078.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acetylation
  • Animals
  • Ataxia Telangiectasia Mutated Proteins
  • Cell Cycle Proteins / metabolism*
  • Cells, Cultured
  • Chromatin Assembly and Disassembly
  • Chromosomal Proteins, Non-Histone / metabolism
  • Chromosome Aberrations
  • DNA Damage
  • DNA Repair
  • DNA-Binding Proteins / metabolism*
  • Enzyme Activation
  • Genomic Instability
  • Histones / metabolism
  • Lymphoma, T-Cell / genetics
  • Mice
  • Mice, Knockout
  • Poly-ADP-Ribose Binding Proteins
  • Protein-Serine-Threonine Kinases / metabolism*
  • Radiation, Ionizing
  • Trans-Activators / metabolism
  • Tumor Suppressor Proteins / chemistry
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*
  • Tumor Suppressor Proteins / physiology*
  • Ubiquitin-Protein Ligases / chemistry
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / physiology*
  • Ubiquitination

Substances

  • Cell Cycle Proteins
  • Chromosomal Proteins, Non-Histone
  • DNA-Binding Proteins
  • Histones
  • MRG15 protein, mouse
  • Poly-ADP-Ribose Binding Proteins
  • Trans-Activators
  • Tumor Suppressor Proteins
  • CHFR protein, mouse
  • Rnf8 protein, mouse
  • Ubiquitin-Protein Ligases
  • Ataxia Telangiectasia Mutated Proteins
  • Atm protein, mouse
  • Protein-Serine-Threonine Kinases