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

• Main Authors: Luciano Gama Braga, Angel F. Cisneros, Michelle M. Mathieu, Maxime Clerc, Pauline Garcia, Baptiste Lottin, Chantal Garand, Philippe Thebault, Christian R. Landry, Sabine Elowe
• Format: Article
• Language: English
• Published: Elsevier 2020-11-01
• Series: Cell Reports
• Subjects: BUBR1; pseudokinase; PP2A; B56; Kinetochore; Spindle checkpoint
• Online Access: http://www.sciencedirect.com/science/article/pii/S2211124720313863

Summary: 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.