title: The SUMO modification pathway is involved in the BRCA1 response to genotoxic stress.
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.
authors.affiliation: Department of Medical and Molecular Genetics, King's College London, Guy's Medical School Campus, London SE1 9RT, UK. jo.morris@genetics.kcl.ac.uk
authors.forename: Joanna R
authors.initials: JR
authors.lastname: Morris
authors.forename: Chris
authors.initials: C
authors.lastname: Boutell
authors.forename: Melanie
authors.initials: M
authors.lastname: Keppler
authors.forename: Ruth
authors.initials: R
authors.lastname: Densham
authors.forename: Daniel
authors.initials: D
authors.lastname: Weekes
authors.forename: Amin
authors.initials: A
authors.lastname: Alamshah
authors.forename: Laura
authors.initials: L
authors.lastname: Butler
authors.forename: Yaron
authors.initials: Y
authors.lastname: Galanty
authors.forename: Laurent
authors.initials: L
authors.lastname: Pangon
authors.forename: Tai
authors.initials: T
authors.lastname: Kiuchi
authors.forename: Tony
authors.initials: T
authors.lastname: Ng
authors.forename: Ellen
authors.initials: E
authors.lastname: Solomon
mesh_terms: D000818:Animals; D019313:BRCA1 Protein / Q000378:metabolism*; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage; D004260:DNA Repair; D006367:HeLa Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D050828:Protein Inhibitors of Activated STAT / Q000378:metabolism; D025841:Small Ubiquitin-Related Modifier Proteins / Q000378:metabolism*; D044763:Ubiquitin-Conjugating Enzymes / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination; D000098843:Ubiquitin-Conjugating Enzyme UBC9
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D006657:Histones; D050828:Protein Inhibitors of Activated STAT; D025841:Small Ubiquitin-Related Modifier Proteins; D044763:Ubiquitin-Conjugating Enzymes; D044767:Ubiquitin-Protein Ligases; D000098843:Ubiquitin-Conjugating Enzyme UBC9