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)

    Research output: Contribution to journalArticle

    209 Citations (Scopus)

    Abstract

    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
    Volume21
    Issue number24
    DOIs
    Publication statusPublished - 16 Dec 2002

    Fingerprint

    Polyubiquitin
    Ubiquitin-Protein Ligases
    Chemical activation
    Histones
    Ubiquitin Thiolesterase
    RING Finger Domains
    Chromosomal Instability
    Nucleosomes
    Zinc Fingers
    DNA Damage
    Zinc
    Tumors
    Phenotype
    Defects
    DNA
    Enzymes
    Neoplasms
    Proteins

    Keywords

    • 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

    Cite this

    Mallery, Donna L. ; Vandenberg, Cassandra J. ; Hiom, Kevin. / Activation of the E3 ligase function of the BRCA1/BARD1 complex by polyubiquitin chains. In: EMBO Journal. 2002 ; Vol. 21, No. 24. pp. 6755-6762.
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    abstract = "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.",
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    Activation of the E3 ligase function of the BRCA1/BARD1 complex by polyubiquitin chains. / Mallery, Donna L.; Vandenberg, Cassandra J.; Hiom, Kevin (Lead / Corresponding author).

    In: EMBO Journal, Vol. 21, No. 24, 16.12.2002, p. 6755-6762.

    Research output: Contribution to journalArticle

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    KW - Genetic vectors

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    KW - Protein binding

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