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 and Ellen Solomon
Additional contact information
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

Nature, 2009, vol. 462, issue 7275, 886-890

Abstract: 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.

Date: 2009
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DOI: 10.1038/nature08593

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