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PMID: 18077395 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Ubc13/Rnf8 ubiquitin ligases control foci formation of the Rap80/Abraxas/Brca1/Brcc36 complex in response to DNA damage.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 104 ·No. 52 ·2007-12-26 ·Pages 20759-63

Wang B, Elledge SJ

Abstract

The Brca1 A complex contains Brca1/Bard1, Abraxas, Rap80, and Brcc36; however, with the exception of the Brca1-Abraxas interaction, how the A complex is assembled is not known. The A complex is localized to sites of DNA damage through the UIM domains of RAP80, which bind K63-linked polyubiquitin chains. In this study, we identified an FHA domain RING finger E3 ubiquitin ligase, RNF8, and an E2-conjugating enzyme known to form K63-polyubiquitin chains, Ubc13, each of which is required to recruit the Brca1 A complex to sites of DNA damage. Rnf8 localizes to sites of DNA damage through an FHA-domain-containing region. We found that Rap80 contains an Abraxas interaction domain [AIR (Abraxas-interacting region)], required for association of Rap80 with Abraxas, Brca1, and Brcc36. Abraxas and Brcc36 associate through coiled-coil domains on each protein. These data suggest a model through which Ubc13 and Rnf8 are recruited to sites of DNA damage through DNA-damage-induced phosphorylation of a chromatin-associated protein and generate polyubiquitin chains that then recruit Rap80 and the entire Brca1 A complex to DNA-damage foci. This sequential E3 ubiquitin ligase recruitment constitutes a ubiquitin ligase cascade required for DNA repair and checkpoint signaling.

MeSH Terms
BRCA1 Protein/metabolism Carrier Proteins/metabolism Cell Line, Tumor DNA Damage DNA-Binding Proteins/chemistry,physiology Deubiquitinating Enzymes Gene Expression Regulation, Neoplastic HeLa Cells Histone Chaperones Humans Membrane Proteins/metabolism Models, Biological Models, Genetic Nuclear Proteins/metabolism Ubiquitin-Conjugating Enzymes/chemistry,physiology Ubiquitin-Protein Ligases
Chemicals
ABRAXAS1 protein, human BRCA1 Protein BRCA1 protein, human Carrier Proteins DNA-Binding Proteins Histone Chaperones Membrane Proteins Nuclear Proteins RNF8 protein, human UIMC1 protein, human UBE2N protein, human Ubiquitin-Conjugating Enzymes Ubiquitin-Protein Ligases BRCC3 protein, human Deubiquitinating Enzymes
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Wang Bin
Department of Genetics, Howard Hughes Medical Institute, Center for Genetics and Genomics, Brigham and Women's Hospital, Harvard University Medical School, Boston, MA 02115, USA.
Elledge Stephen J
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
1091-6490
DOI
10.1073/pnas.0710061104
Published
2007-12-26
Epub
2007-00-05
Pages
20759-63
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC2410075
Subset
IM
Grants
NCI NIH HHS · K01 CA116275 · United States
NCI NIH HHS · 1KO1 CA116275-01 · United States
Corrections
CommentIn
PMID: 18093907
External Links
PubMed source DOI: 10.1073/pnas.0710061104 PMC Full Text View journal details
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