Three-Dimensional Architecture of the Human BRCA1-A Histone Deubiquitinase Core Complex

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.

New Insights into Protein Kinase B/Akt Signaling: Role of Localized Akt Activation and Compartment-Specific Target Proteins for the Cellular Radiation Response

“…The HRR protein BRCA1 is frequently mutated in cancer and was described as a biomarker in breast and ovarian cancer [ 252 , 253 ]. BRCA1 forms diverse complexes, e.g., BRCA1-A, BRCA1-B, BRCA1-C, and the BRCA1/PALB2/BRCA2 complex, and plays diverse roles in the regulation of checkpoint activation, repair pathway choice, and HRR efficiency in a context-dependent manner [ 254 , 255 ].…”

“…One of these complexes, BRCA1-A, seems to be critical for the accumulation of BRCA1 at sites of DNA damage. BRCA1-A involves the ubiquitin-binding motif (UIM)-containing protein RAP80, the coiled-coil domain protein CCDC98/Abraxas, the deubiquitinating enzyme BRCC36, as well as BRCC45, BARD1, and MERIT40 [ 252 , 254 , 256 ]. MERIT40 positively influences HRR by enhancing assembly and stability of BRCA1 complexes at sites of DNA damage ends [ 256 , 257 ].…”

C-terminal BRE overexpression in 11q23-rearranged and t(8;16) acute myeloid leukemia is caused by intragenic transcription initiation

“…26 BRE is required for proper function of the BRCA-1-A and BRISC complexes, which are involved in DNA repair and cell cycle regulation. 14,[17][18][19][20]35,36 Another important constituent of these complexes is BRCC3. Mutations in BRCC3 and other components of these two complexes have recently been observed in myeloid malignancies, including AML.…”

“…BRE functions in BRCA-1 (breast cancer 1)-mediated DNA damage repair, BRISC (BRCC3 isopeptidase complex)-mediated deubiquitination and in protection from apoptosis and senescence. [13][14][15][16][17][18][19][20] Its exact function in hematopoiesis remains to be determined. Importantly, it is currently unknown how BRE overexpression is caused in KMT2A-MLLT3 AML.…”

Pseudo-DUBs as allosteric activators and molecular scaffolds of protein complexes

“…The MPN family DUBs regulate diverse aspects of cellular biology, most notably DNA repair through BRCC36 (MPN + ) in the BRCA1-A complex (BRCC36-ABRAXAS1-BRCC45-MERIT40-RAP80 complex) [29,[36][37][38] , interferon receptor signalling through BRCC36 (MPN + ) in the BRISC-SHMT2 complex (BRCC36-ABRAXAS2-BRCC45-MERIT40 complex) [32,39] (Fig. 3), and protein degradation through Rpn11/PSMD14 (MPN + ) in the proteasome lid complex [40] .…”