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Download fileThree-dimensional architecture of the human BRCA1-A histone deubiquitinase core complex
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posted on 2020-08-20, 16:28 authored by Otto JP 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 SmerdonBRCA1 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.
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BRCA1BRCA1-ADNA repairDNA-damage checkpointDNA-damage signalingcancerdeubiquitinaseelectron microscopyhomologous recombinationstructural biologyAtaxia Telangiectasia Mutated ProteinsBRCA1 ProteinBreast NeoplasmsCarrier ProteinsChromatinDNA DamageDNA RepairDeubiquitinating EnzymesGenomic InstabilityHistonesHumansMultiprotein ComplexesProtein BindingProtein ConformationProtein MultimerizationRecombinational DNA RepairUbiquitinSmerdon FC001156Rosenthal FC001143SB0601 Biochemistry and Cell Biology