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- Title
The SUMO modification pathway is involved in the BRCA1 response to genotoxic stress.
- Authors
Morris, Joanna R.; Boutell, Chris; Keppler, Melanie; Densham, Ruth; Weekes, Daniel; Alamshah, Amin; Butler, Laura; Galanty, Yaron; Pangon, Laurent; Kiuchi, Tai; Ng, Tony; Solomon, Ellen
- 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.
- Subjects
GENETIC toxicology; BRCA genes; TUMOR suppressor genes; DNA damage; BREAST cancer; OVARIAN cancer; UBIQUITIN; LIGASES; ENZYMES
- Publication
Nature, 2009, Vol 462, Issue 7275, p886
- ISSN
0028-0836
- Publication type
Article
- DOI
10.1038/nature08593