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

Donna L. Mallery, Cassandra J. Vandenberg, Kevin Hiom (Lead / Corresponding author)

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    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.

    Original languageEnglish
    Pages (from-to)6755-6762
    Number of pages8
    JournalEMBO Journal
    Issue number24
    Publication statusPublished - 16 Dec 2002



    • BRCA1 protein
    • Carrier proteins
    • Catalysis
    • DNA damage
    • Electrophoresis, Polyacrylamide Gel
    • Enzyme activation
    • Genetic vectors
    • Histones
    • Humans
    • Protein binding
    • Protein structure, Tertiary
    • Recombinant proteins
    • Substrate specificity
    • Tumor suppressor proteins
    • Ubiquitin
    • Ubiquitin-protein ligases
    • Zinc fingers

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