Journal
NATURE
Volume 462, Issue 7275, Pages 886-U77Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature08593
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Funding
- Breast Cancer Campaign [SF06, 06NovPHD13Morris]
- Cancer Research UK [C8820/A9494]
- Medical Research Council [6900577]
- Richard Dimbleby Cancer Fund
- Breakthrough Breast Cancer
- MRC Co-operative Group [G0100152, 56891]
- UK Research Councils Basic Technology Research Programme [GR/R87901/01]
- MRC [G9600577] Funding Source: UKRI
- Engineering and Physical Sciences Research Council [GR/R87901/01] Funding Source: researchfish
- Medical Research Council [G9600577] Funding Source: researchfish
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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.
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