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

    310 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 - 2009 Dec 17

    ASJC Scopus subject areas

    • General

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