The deubiquitinating enzyme complex BRISC is required for proper mitotic spindle assembly in mammalian cells

J Cell Biol. 2015 Jul 20;210(2):209-24. doi: 10.1083/jcb.201503039.

Abstract

Deubiquitinating enzymes (DUBs) negatively regulate protein ubiquitination and play an important role in diverse physiological processes, including mitotic division. The BRCC36 isopeptidase complex (BRISC) is a DUB that is specific for lysine 63-linked ubiquitin hydrolysis; however, its biological function remains largely undefined. Here, we identify a critical role for BRISC in the control of mitotic spindle assembly in cultured mammalian cells. BRISC is a microtubule (MT)-associated protein complex that predominantly localizes to the minus ends of K-fibers and spindle poles and directly binds to MTs; importantly, BRISC promotes the assembly of functional bipolar spindle by deubiquitinating the essential spindle assembly factor nuclear mitotic apparatus (NuMA). The deubiquitination of NuMA regulates its interaction with dynein and importin-β, which are required for its function in spindle assembly. Collectively, these results uncover BRISC as an important regulator of the mitotic spindle assembly and cell division, and have important implications for the development of anticancer drugs targeting BRISC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Antigens, Nuclear / metabolism
  • Cell Cycle Proteins
  • Deubiquitinating Enzymes
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Kinetochores / metabolism
  • M Phase Cell Cycle Checkpoints
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Microtubules / metabolism
  • Multienzyme Complexes / physiology*
  • Nuclear Matrix-Associated Proteins / genetics
  • Nuclear Matrix-Associated Proteins / metabolism*
  • Protein Transport
  • Spindle Apparatus / metabolism*
  • Ubiquitin-Specific Proteases / genetics
  • Ubiquitin-Specific Proteases / metabolism*
  • Ubiquitination*

Substances

  • ABRAXAS2 protein, human
  • Adaptor Proteins, Signal Transducing
  • Antigens, Nuclear
  • BABAM1 protein, human
  • Cell Cycle Proteins
  • Membrane Proteins
  • Multienzyme Complexes
  • NUMA1 protein, human
  • Nuclear Matrix-Associated Proteins
  • BRCC3 protein, human
  • Deubiquitinating Enzymes
  • Ubiquitin-Specific Proteases