BUBR1 Pseudokinase Domain Promotes Kinetochore PP2A-B56 Recruitment, Spindle Checkpoint Silencing, and Chromosome Alignment

Cell Rep. 2020 Nov 17;33(7):108397. doi: 10.1016/j.celrep.2020.108397.

Abstract

The balance of phospho-signaling at the outer kinetochore is critical for forming accurate attachments between kinetochores and the mitotic spindle and timely exit from mitosis. A major player in determining this balance is the PP2A-B56 phosphatase, which is recruited to the kinase attachment regulatory domain (KARD) of budding uninhibited by benzimidazole 1-related 1 (BUBR1) in a phospho-dependent manner. This unleashes a rapid, switch-like phosphatase relay that reverses mitotic phosphorylation at the kinetochore, extinguishing the checkpoint and promoting anaphase. Here, we demonstrate that the C-terminal pseudokinase domain of human BUBR1 is required to promote KARD phosphorylation. Mutation or removal of the pseudokinase domain results in decreased PP2A-B56 recruitment to the outer kinetochore attenuated checkpoint silencing and errors in chromosome alignment as a result of imbalance in Aurora B activity. Our data, therefore, elucidate a function for the BUBR1 pseudokinase domain in ensuring accurate and timely exit from mitosis.

Keywords: B56; BUBR1; Kinetochore; PP2A; SAC; Spindle checkpoint; evolution; pseudokinase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Cycle Checkpoints / physiology
  • Cell Cycle Proteins / metabolism
  • Chromosomes / metabolism
  • HeLa Cells
  • Humans
  • Kinetochores / metabolism
  • M Phase Cell Cycle Checkpoints / genetics
  • M Phase Cell Cycle Checkpoints / physiology*
  • Mitosis
  • Phosphorylation
  • Protein Binding
  • Protein Domains / genetics
  • Protein Phosphatase 2 / metabolism*
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • Spindle Apparatus / metabolism

Substances

  • Cell Cycle Proteins
  • BUB1 protein, human
  • Protein Serine-Threonine Kinases
  • PP2A-B56alpha protein, human
  • Protein Phosphatase 2