title: Three-Dimensional Architecture of the Human BRCA1-A Histone Deubiquitinase Core Complex.
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.
authors.affiliation: Structural Biology of DNA-Damage Signalling Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
authors.forename: Otto J P
authors.initials: OJP
authors.lastname: Kyrieleis
authors.affiliation: Structural Biology of Cells and Viruses Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
authors.forename: Pauline B
authors.initials: PB
authors.lastname: McIntosh
authors.affiliation: Structural Biology of DNA-Damage Signalling Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Webb
authors.affiliation: Structural Biology of Cells and Viruses Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
authors.forename: Lesley J
authors.initials: LJ
authors.lastname: Calder
authors.affiliation: Structural Biology of DNA-Damage Signalling Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
authors.forename: Janette
authors.initials: J
authors.lastname: Lloyd
authors.affiliation: Department of Chemistry, Physical and Theoretical Chemistry Laboratory, University of Oxford, South Parks Road, OX1 3QZ Oxford, UK.
authors.forename: Nisha A
authors.initials: NA
authors.lastname: Patel
authors.affiliation: Structural Biology Technology Platform, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Martin
authors.affiliation: Department of Chemistry, Physical and Theoretical Chemistry Laboratory, University of Oxford, South Parks Road, OX1 3QZ Oxford, UK.
authors.forename: Carol V
authors.initials: CV
authors.lastname: Robinson
authors.affiliation: Structural Biology of Cells and Viruses Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK. Electronic address: peter.rosenthal@crick.ac.uk.
authors.forename: Peter B
authors.initials: PB
authors.lastname: Rosenthal
authors.affiliation: Structural Biology of DNA-Damage Signalling Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK. Electronic address: steve.smerdon@crick.ac.uk.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Smerdon
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000737:chemistry / Q000235:genetics; D019313:BRCA1 Protein / Q000737:chemistry* / Q000235:genetics / Q000648:ultrastructure; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology; D002352:Carrier Proteins / Q000737:chemistry* / Q000235:genetics / Q000648:ultrastructure; D002843:Chromatin / Q000737:chemistry / Q000235:genetics; D004249:DNA Damage / Q000235:genetics; D004260:DNA Repair / Q000235:genetics; D000072017:Deubiquitinating Enzymes / Q000737:chemistry* / Q000235:genetics / Q000648:ultrastructure; D042822:Genomic Instability; D006657:Histones / Q000737:chemistry* / Q000235:genetics; D006801:Humans; D046912:Multiprotein Complexes / Q000737:chemistry* / Q000235:genetics / Q000648:ultrastructure; D011485:Protein Binding; D011487:Protein Conformation; D055503:Protein Multimerization; D059767:Recombinational DNA Repair / Q000235:genetics; D025801:Ubiquitin / Q000235:genetics
chemical_list: C520310:ABRAXAS1 protein, human; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D002352:Carrier Proteins; D002843:Chromatin; D006657:Histones; D046912:Multiprotein Complexes; D025801:Ubiquitin; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D000072017:Deubiquitinating Enzymes
keywords: BRCA1; BRCA1-A; DNA repair; DNA-damage checkpoint; DNA-damage signaling; cancer; deubiquitinase; electron microscopy; homologous recombination; structural biology