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

Research output: Contribution to journalArticle

Authors

  • C Boutell
  • M Keppler
  • D Weekes
  • A Alamshah
  • Laura Butler
  • Y Galanty
  • L Pangon
  • T Kiuchi
  • T Ng
  • E Solomon

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.

Details

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