Three-dimensional architecture of the human BRCA1-A histone deubiquitinase core complex
Research output: Contribution to journal › Article
Colleges, School and Institutes
- Structural Biology of DNA-damage Signalling Laboratory, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK.
- Structural Biology of Cells and Viruses Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
- Department of Chemistry, Physical and Theoretical Chemistry Laboratory, University of Oxford, South Parks Road, OX1 3QZ Oxford, UK.
- Structural Biology Science Technology Platform, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK.
- Structural Biology of Cells and Viruses Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK. Electronic address: email@example.com.
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.
|Number of pages||8|
|Publication status||Published - 20 Dec 2016|
- 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