Structural Basis of BRCC36 Function in DNA Repair and Immune Regulation

Julius Rabl, Richard D. Bunker, Andreas D. Schenk, Simone Cavadini, Mark E. Gill, Wassim Abdulrahman, Amparo Andrés-Pons, Martijn S. Luijsterburg, Adel F. M. Ibrahim, Emma Branigan, Jacob D. Aguirre, Aimee H. Marceau, Claire Guérillon, Tewis Bouwmeester, Ulrich Hassiepen, Antoine H. F. M. Peters, Martin Renatus, Laurent Gelman, Seth M. Rubin, Niels MailandHaico van Attikum, Ronald T. Hay, Nicolas H. Thomä

Research output: Contribution to journalArticle

2 Citations (Scopus)
88 Downloads (Pure)

Abstract

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.
Original languageEnglish
Pages (from-to)483-497.e9
Number of pages15
JournalMolecular Cell
Volume75
Issue number3
Early online date25 Jun 2019
DOIs
Publication statusPublished - 8 Aug 2019

Keywords

  • BRCA1-A
  • BRISC
  • DNA repair
  • SHMT2
  • deubiquitination
  • regulation
  • ubiquitin signaling

Fingerprint Dive into the research topics of 'Structural Basis of BRCC36 Function in DNA Repair and Immune Regulation'. Together they form a unique fingerprint.

  • Cite this

    Rabl, J., Bunker, R. D., Schenk, A. D., Cavadini, S., Gill, M. E., Abdulrahman, W., Andrés-Pons, A., Luijsterburg, M. S., Ibrahim, A. F. M., Branigan, E., Aguirre, J. D., Marceau, A. H., Guérillon, C., Bouwmeester, T., Hassiepen, U., Peters, A. H. F. M., Renatus, M., Gelman, L., Rubin, S. M., ... Thomä, N. H. (2019). Structural Basis of BRCC36 Function in DNA Repair and Immune Regulation. Molecular Cell, 75(3), 483-497.e9. https://doi.org/10.1016/j.molcel.2019.06.002