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

Bin Wang, Stephen J. Elledge

Research output: Contribution to journalArticlepeer-review

373 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)20759-20763
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number52
DOIs
StatePublished - Dec 26 2007
Externally publishedYes

Keywords

  • 53BP1
  • Breast cancer
  • K63
  • Mdc1
  • Ubiquitination

ASJC Scopus subject areas

  • General

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