The SUMO modification pathway is involved in the BRCA1 response to genotoxic stress

Nature. 2009 Dec 17;462(7275):886-90. doi: 10.1038/nature08593.

Abstract

Mutations in BRCA1 are associated with a high risk of breast and ovarian cancer. BRCA1 participates in the DNA damage response and acts as a ubiquitin ligase. However, its regulation remains poorly understood. Here we report that BRCA1 is modified by small ubiquitin-like modifier (SUMO) in response to genotoxic stress, and co-localizes at sites of DNA damage with SUMO1, SUMO2/3 and the SUMO-conjugating enzyme Ubc9. PIAS SUMO E3 ligases co-localize with and modulate SUMO modification of BRCA1, and are required for BRCA1 ubiquitin ligase activity in cells. In vitro SUMO modification of the BRCA1/BARD1 heterodimer greatly increases its ligase activity, identifying it as a SUMO-regulated ubiquitin ligase (SRUbL). Further, PIAS SUMO ligases are required for complete accumulation of double-stranded DNA (dsDNA) damage-repair proteins subsequent to RNF8 accrual, and for proficient double-strand break repair. These data demonstrate that the SUMOylation pathway plays a significant role in mammalian DNA damage response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • BRCA1 Protein / metabolism*
  • COS Cells
  • Cell Line
  • Chlorocebus aethiops
  • DNA Breaks, Double-Stranded
  • DNA Damage*
  • DNA Repair
  • HeLa Cells
  • Histones / metabolism
  • Humans
  • Protein Inhibitors of Activated STAT / metabolism
  • Small Ubiquitin-Related Modifier Proteins / metabolism*
  • Ubiquitin-Conjugating Enzymes / metabolism
  • Ubiquitin-Protein Ligases / metabolism
  • Ubiquitination

Substances

  • BRCA1 Protein
  • BRCA1 protein, human
  • Histones
  • Protein Inhibitors of Activated STAT
  • Small Ubiquitin-Related Modifier Proteins
  • Ubiquitin-Conjugating Enzymes
  • Ubiquitin-Protein Ligases
  • ubiquitin-conjugating enzyme UBC9