Structural Basis of BRCC36 Function in DNA Repair and Immune Regulation

Mol Cell. 2019 Aug 8;75(3):483-497.e9. doi: 10.1016/j.molcel.2019.06.002. Epub 2019 Jun 25.


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.

Keywords: BRCA1-A; BRISC; DNA repair; SHMT2; deubiquitination; regulation; ubiquitin signaling.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • BRCA1 Protein / genetics*
  • Binding Sites / genetics
  • Carrier Proteins / genetics
  • Cell Nucleus / genetics
  • Cell Nucleus / immunology
  • Cytoplasm / genetics
  • Cytoplasm / immunology
  • DNA Breaks, Double-Stranded
  • DNA Repair / genetics*
  • DNA Repair / immunology
  • DNA-Binding Proteins / genetics*
  • Deubiquitinating Enzymes / genetics*
  • Deubiquitinating Enzymes / immunology
  • HeLa Cells
  • Histone Chaperones / genetics*
  • Humans
  • Immunity, Cellular / genetics
  • Multiprotein Complexes / chemistry
  • Multiprotein Complexes / genetics
  • Neoplasms / genetics*
  • Neoplasms / immunology
  • Nuclear Matrix-Associated Proteins / genetics
  • Protein Binding / genetics
  • Ubiquitin / genetics
  • Ubiquitin-Specific Proteases / genetics
  • Ubiquitination / genetics


  • ABRAXAS1 protein, human
  • ABRAXAS2 protein, human
  • BRCA1 Protein
  • BRCA1 protein, human
  • Carrier Proteins
  • DNA-Binding Proteins
  • Histone Chaperones
  • Multiprotein Complexes
  • Nuclear Matrix-Associated Proteins
  • UIMC1 protein, human
  • Ubiquitin
  • BRCC3 protein, human
  • Deubiquitinating Enzymes
  • Ubiquitin-Specific Proteases