Activation of the E3 ligase function of the BRCA1/BARD1 complex by polyubiquitin chains

EMBO J. 2002 Dec 16;21(24):6755-62. doi: 10.1093/emboj/cdf691.


Loss of the tumour suppressor BRCA1 results in profound chromosomal instability. The fundamental defect underlying this catastrophic phenotype is not yet known. In vivo, BRCA1 forms a heterodimeric complex with BARD1. Both proteins contain an N-terminal zinc RING-finger domain which confers E3 ubiquitin ligase activity. We have isolated full-length human BRCA1/BARD1 complex and have shown that it has a dual E3 ubiquitin ligase activity. First, it mediates the monoubiquitylation of nucleosome core histones in vitro, including the variant histone H2AX that co-localizes with BRCA1 at sites of DNA damage. Secondly, BRCA1/BARD1 catalyses the formation of multiple polyubiquitin chains on itself. Remarkably, this auto-polyubiquitylation potentiates the E3 ubiquitin ligase activity of the BRCA1/BARD1 complex >20-fold. Even though BRCA1 has been reported to associate with a C-terminal ubiquitin hydrolase, BAP1, this enzyme does not appear to function in the deubiquitylation of the BRCA1/BARD1 complex.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • BRCA1 Protein / chemistry*
  • BRCA1 Protein / metabolism*
  • Carrier Proteins / chemistry*
  • Carrier Proteins / metabolism
  • Catalysis
  • DNA Damage
  • Electrophoresis, Polyacrylamide Gel
  • Enzyme Activation
  • Genetic Vectors
  • Histones / metabolism
  • Humans
  • Protein Binding
  • Protein Structure, Tertiary
  • Recombinant Proteins / metabolism
  • Substrate Specificity
  • Tumor Suppressor Proteins*
  • Ubiquitin / metabolism
  • Ubiquitin-Protein Ligases / metabolism*
  • Zinc Fingers


  • BRCA1 Protein
  • Carrier Proteins
  • Histones
  • Recombinant Proteins
  • Tumor Suppressor Proteins
  • Ubiquitin
  • BARD1 protein, human
  • Ubiquitin-Protein Ligases