Abstract
SummaryBRCA1 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.
Highlights
Among the various types of genotoxic DNA lesions encountered by human cells, double-stranded DNA breaks (DSBs) are the most deleterious, because failure to faithfully repair them can result in a variety of mutations, including chromosomal rearrangements that are characteristic of cancer cells
We present the structure of a catalytically active BRCA1-A core complex consisting of Abraxas, Brcc36, Brcc45, and Merit40 determined by single particle negative-stain electron microscopy (EM)
We were successful in reconstituting a four-component ‘‘core’’ assembly of Abraxas/ BRCC36/BRCC45/MERIT40 from two bacterially expressed subcomplexes containing BRCC36 and an Abraxas fragment, and full-length BRCC45/MERIT40
Summary
Among the various types of genotoxic DNA lesions encountered by human cells, double-stranded DNA breaks (DSBs) are the most deleterious, because failure to faithfully repair them can result in a variety of mutations, including chromosomal rearrangements that are characteristic of cancer cells. The subsequent MDC1-dependent recruitment of the ubiquitin E3 ligases RNF8 and RNF168 together with the E2-conjugating enzyme UBC13/ MMS2 results in K63-linked polyubiquitination of histones H2A and H2AX (Al-Hakim et al, 2010; Kolas et al, 2007; Panier and Durocher, 2009). These ubiquitin (Ub) chains provide the binding site for the ubiquitin-interacting motif (UIM) of the fifth BRCA1-A component, Rap (Sato et al, 2009). BRCC36, BRCC45, and Merit proteins are found in complex with an Abraxas paralog, Abro1/KIAA0157 (Feng et al, 2010; Patterson-Fortin et al, 2010), and an adaptor
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
