Regulation of BRCC, a holoenzyme complex containing BRCA1 and BRCA2, by a signalosome-like subunit and its role in DNA repair

Yuanshu Dong, Mohamed Ali Hakimi, Xiaowei Chen, Easwari Kumaraswamy, Neil S. Cooch, Andrew K. Godwin, Ramin Shiekhattar

Research output: Contribution to journalArticlepeer-review

207 Scopus citations

Abstract

We have isolated a holoenzyme complex termed BRCC containing BRCA1, BRCA2, and RAD51. BRCC not only displays increased association with p53 following DNA damage but also ubiquitinates p53 in vitro. BRCC36 and BRCC45 are novel components of the complex with sequence homology to a subunit of the signalosome and proteasome complexes. Reconstitution of a recombinant four-subunit complex containing BRCA1/BARD1/BRCC45/BRCC36 revealed an enhanced E3 ligase activity compared to that of BRCA1/BARD1 heterodimer. In vivo, depletion of BRCC36 and BRCC45 by the small interfering RNAs (siRNAs) resulted in increased sensitivity to ionizing radiation and defects in G2/M checkpoint. BRCC36 shows aberrant expression in sporadic breast tumors. These findings identify BRCC as a ubiquitin E3 ligase complex that enhances cellular survival following DNA damage.

Original languageEnglish (US)
Pages (from-to)1087-1099
Number of pages13
JournalMolecular Cell
Volume12
Issue number5
DOIs
StatePublished - Nov 2003
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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