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

Author

Listed:
  • Joanna R. Morris

    (King’s College London, Guy’s Medical School Campus)

  • Chris Boutell

    (MRC Virology Unit, Church Street, Glasgow G11 5JR, Scotland, UK)

  • Melanie Keppler

    (King’s College London, Guy’s Medical School Campus)

  • Ruth Densham

    (King’s College London, Guy’s Medical School Campus)

  • Daniel Weekes

    (King’s College London, Guy’s Medical School Campus)

  • Amin Alamshah

    (King’s College London, Guy’s Medical School Campus)

  • Laura Butler

    (King’s College London, Guy’s Medical School Campus)

  • Yaron Galanty

    (University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK)

  • Laurent Pangon

    (King’s College London, Guy’s Medical School Campus)

  • Tai Kiuchi

    (King’s College London, Guy’s Medical School Campus)

  • Tony Ng

    (King’s College London, Guy’s Medical School Campus)

  • Ellen Solomon

    (King’s College London, Guy’s Medical School Campus)

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.

Suggested Citation

  • 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, 2009. "The SUMO modification pathway is involved in the BRCA1 response to genotoxic stress," Nature, Nature, vol. 462(7275), pages 886-890, December.
    • Handle: RePEc:nat:nature:v:462:y:2009:i:7275:d:10.1038_nature08593
    DOI: 10.1038/nature08593
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