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

Joanna R. Morris, Chris Boutell, Melanie Keppler, Ruth Densham, Daniel Weekes, Amin Alamshah, Laura Butler, Yaron Galanty, Laurent Pangon, Tai Kiuchi, Tony Ng, Ellen Solomon

Research output: Contribution to journalArticlepeer-review

350 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)886 - 890
Number of pages5
JournalNATURE
Volume462
Issue number7275
DOIs
Publication statusPublished - 17 Dec 2009

Keywords

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

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