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The SUMO modification pathway is involved in the BRCA1 response to genotoxic stress
Joanna R. Morris1,5, Chris Boutell2,5, Melanie Keppler3,5, Ruth Densham1, Daniel Weekes1, Amin Alamshah1, Laura Butler1, Yaron Galanty4, Laurent Pangon1, Tai Kiuchi3, Tony Ng3 & Ellen Solomon1
1 Department of Medical and Molecular Genetics, King’s College London, Guy’s Medical School Campus, London SE1 9RT, UK
2 MRC Virology Unit, Church Street, Glasgow G11 5JR, Scotland, UK
3 Richard Dimbleby Department of Cancer Research, Randall Division of Cell and Molecular Biophysics, King’s College London, Guy’s Medical School Campus, London SE1 1UL, UK
4 The Wellcome Trust/Cancer Research UK Gurdon Institute and Department of Zoology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK
5 These authors contributed equally to this work.
Correspondence to: Joanna R. Morris1,5 Correspondence and requests for materials should be addressed to J.R.M.
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.
