Three-dimensional architecture of the human BRCA1-A histone deubiquitinase core complex

Otto J P Kyrieleis, Pauline B McIntosh, Sarah R Webb, Lesley J Calder, Janette Lloyd, Nisha A Patel, Stephen R Martin, Carol V Robinson, Peter B Rosenthal, Stephen J Smerdon

Research output: Contribution to journalArticlepeer-review

14 Citations (Scopus)
90 Downloads (Pure)

Abstract

BRCA1 is a tumor suppressor found to be mutated in hereditary breast and ovarian cancer and plays key roles in the maintenance of genomic stability by homologous recombination repair. It is recruited to damaged chromatin as a component of the BRCA1-A deubiquitinase, which cleaves K63-linked ubiquitin chains attached to histone H2A and H2AX. BRCA1-A contributes to checkpoint regulation, repair pathway choice, and HR repair efficiency through molecular mechanisms that remain largely obscure. The structure of an active core complex comprising two Abraxas/BRCC36/BRCC45/MERIT40 tetramers determined by negative-stain electron microscopy (EM) reveals a distorted V-shape architecture in which a dimer of Abraxas/BRCC36 heterodimers sits at the base, with BRCC45/Merit40 pairs occupying each arm. The location and ubiquitin-binding activity of BRCC45 suggest that it may provide accessory interactions with nucleosome-linked ubiquitin chains that contribute to their efficient processing. Our data also suggest how ataxia telangiectasia mutated (ATM)-dependent BRCA1 dimerization may stabilize self-association of the entire BRCA1-A complex.

Original languageEnglish
Pages (from-to)3099-3106
Number of pages8
JournalCell Reports
Volume17
Issue number12
DOIs
Publication statusPublished - 20 Dec 2016

Keywords

  • Ataxia Telangiectasia Mutated Proteins/chemistry
  • BRCA1 Protein/chemistry
  • Breast Neoplasms/genetics
  • Carrier Proteins/chemistry
  • Chromatin/chemistry
  • DNA Damage/genetics
  • DNA Repair/genetics
  • Deubiquitinating Enzymes/chemistry
  • Genomic Instability
  • Histones/chemistry
  • Humans
  • Multiprotein Complexes/chemistry
  • Protein Binding
  • Protein Conformation
  • Protein Multimerization
  • Recombinational DNA Repair/genetics
  • Ubiquitin/genetics

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