1. Structural Basis of BRCC36 Function in DNA Repair and Immune Regulation
- Author
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W. Abdulrahman, Adel F. M. Ibrahim, Ronald T. Hay, Martin Renatus, Aimee H. Marceau, Ulrich Hassiepen, Simone Cavadini, Antoine H.F.M. Peters, Seth M. Rubin, Julius Rabl, Jacob D. Aguirre, Tewis Bouwmeester, Richard D. Bunker, Nicolas H. Thomä, H. van Attikum, Niels Mailand, M.E. Gill, Andreas D. Schenk, Emma Branigan, Claire Guérillon, A. Andres-Pons, L. Gelman, and Luijsterburg
- Subjects
Cytoplasm ,DNA Repair ,DNA repair ,Protein subunit ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Ubiquitin ,Nuclear Matrix-Associated Proteins ,Neoplasms ,DNA Repair Protein ,BRISC ,Humans ,DNA Breaks, Double-Stranded ,Histone Chaperones ,BRCA1-A ,Ubiquitin signaling ,Deubiquitination ,Regulation ,SHMT2 ,Binding site ,Molecular Biology ,deubiquitination ,030304 developmental biology ,Cell Nucleus ,0303 health sciences ,Immunity, Cellular ,Binding Sites ,biology ,Deubiquitinating Enzymes ,BRCA1 Protein ,Ubiquitination ,regulation ,Cell Biology ,ubiquitin signaling ,Cell biology ,DNA-Binding Proteins ,chemistry ,Multiprotein Complexes ,biology.protein ,Ubiquitin-Specific Proteases ,Carrier Proteins ,030217 neurology & neurosurgery ,Function (biology) ,DNA ,HeLa Cells ,Protein Binding - Abstract
Summary In mammals, ∼100 deubiquitinases act on ∼20,000 intracellular ubiquitination sites. Deubiquitinases are commonly regarded as constitutively active, with limited regulatory and targeting capacity. The BRCA1-A and BRISC complexes serve in DNA double-strand break repair and immune signaling and contain the lysine-63 linkage-specific BRCC36 subunit that is functionalized by scaffold subunits ABRAXAS and ABRO1, respectively. The molecular basis underlying BRCA1-A and BRISC function is currently unknown. Here we show that in the BRCA1-A complex structure, ABRAXAS integrates the DNA repair protein RAP80 and provides a high-affinity binding site that sequesters the tumor suppressor BRCA1 away from the break site. In the BRISC structure, ABRO1 binds SHMT2α, a metabolic enzyme enabling cancer growth in hypoxic environments, which we find prevents BRCC36 from binding and cleaving ubiquitin chains. Our work explains modularity in the BRCC36 DUB family, with different adaptor subunits conferring diversified targeting and regulatory functions., Graphical Abstract, Highlights • Detailed structural studies of the BRCA1-A and BRISC-SHMT2 protein complex • Complex-specific subunits functionalize BRCC36, regulating its activity and targeting • BRCA1-A sequesters BRCA1 with nanomolar affinity • Cancer-associated metabolic enzyme SHMT2 inhibits BRISC deubiquitination activity, Structural studies of the BRCA1-A and BRISC complexes reveal a common enzymatic core that is functionalized by complex-specific proteins. BRCA1-A localizes to DNA double-strand breaks, sequesters BRCA1, and suppresses DNA resection. BRISC regulates protein degradation by the endosomal-lysosomal pathway through deubiquitination and is inhibited by the metabolic enzyme SHMT2.
- Published
- 2019