Content-Length: 26711 | pFad | http://www.ncbi.nlm.nih.gov/pubmed/19203579

000 RNF168 binds and amplifies ubiquitin conjugates on damaged chromosomes to allow accumulation of repair proteins

RNF168 binds and amplifies ubiquitin conjugates on damaged chromosomes to allow accumulation of repair proteins

Cell. 2009 Feb 6;136(3):435-46. doi: 10.1016/j.cell.2008.12.041.

Abstract

DNA double-strand breaks (DSBs) not only interrupt the genetic information, but also disrupt the chromatin structure, and both impairments require repair mechanisms to ensure genome integrity. We showed previously that RNF8-mediated chromatin ubiquitylation protects genome integrity by promoting the accumulation of repair factors at DSBs. Here, we provide evidence that, while RNF8 is necessary to trigger the DSB-associated ubiquitylations, it is not sufficient to sustain conjugated ubiquitin in this compartment. We identified RNF168 as a novel chromatin-associated ubiquitin ligase with an ability to bind ubiquitin. We show that RNF168 interacts with ubiquitylated H2A, assembles at DSBs in an RNF8-dependent manner, and, by targeting H2A and H2AX, amplifies local concentration of lysine 63-linked ubiquitin conjugates to the threshold required for retention of 53BP1 and BRCA1. Thus, RNF168 defines a new pathway involving sequential ubiquitylations on damaged chromosomes and uncovers a functional cooperation between E3 ligases in genome maintenance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Chromosomes / metabolism*
  • DNA Breaks, Double-Stranded*
  • DNA Repair*
  • DNA-Binding Proteins / metabolism
  • Gene Knockdown Techniques
  • Histones / metabolism
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Protein Structure, Tertiary
  • Tumor Suppressor p53-Binding Protein 1
  • Ubiquitin / metabolism*
  • Ubiquitin-Protein Ligases / chemistry
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*

Substances

  • DNA-Binding Proteins
  • Histones
  • Intracellular Signaling Peptides and Proteins
  • RNF8 protein, human
  • TP53BP1 protein, human
  • Tumor Suppressor p53-Binding Protein 1
  • Ubiquitin
  • RNF168 protein, human
  • Ubiquitin-Protein Ligases








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