scholarly journals The BUBR1 pseudokinase domain promotes efficient kinetochore PP2A-B56 recruitment to regulate spindle checkpoint silencing and chromosome alignment

2019 ◽  
Author(s):  
Luciano Gama Braga ◽  
Angel F. Cisneros ◽  
Michelle Mathieu ◽  
Maxime Clerc ◽  
Pauline Garcia ◽  
...  

ABSTRACTThe balance of phospho-signalling at outer-kinetochores during mitosis is critical for the accurate attachments between kinetochores and the mitotic spindle and timely exit from mitosis. In humans, a major player in determining this balance is the PP2A-B56 phosphatase which is recruited to the Kinase Attachment Regulatory Domain (KARD) of the Spindle Assembly Checkpoint protein Budding Uninhibited by Benzimidazole 1-related 1 (BUBR1) in a phospho-dependent manner. This event unleashes a rapid, switch-like phosphatase relay that reverses phosphorylation at the kinetochore, extinguishing the checkpoint and promoting anaphase entry. Here, we conclusively demonstrate that the pseudokinase domain of human BUBR1 lacks phosphotransfer activity and that it was maintained in vertebrates because it allosterically promotes KARD phosphorylation. Mutation or removal of this 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. We demonstrate that the functions of the BUBR1 pseudokinase and the BUB1 kinase domains are intertwined, providing an explanation for retention of the pseudokinase domain in certain eukaryotes.

2007 ◽  
Vol 179 (4) ◽  
pp. 601-609 ◽  
Author(s):  
Emilie Montembault ◽  
Stéphanie Dutertre ◽  
Claude Prigent ◽  
Régis Giet

The spindle checkpoint delays anaphase onset until every chromosome kinetochore has been efficiently captured by the mitotic spindle microtubules. In this study, we report that the human pre–messenger RNA processing 4 (PRP4) protein kinase associates with kinetochores during mitosis. PRP4 depletion by RNA interference induces mitotic acceleration. Moreover, we frequently observe lagging chromatids during anaphase leading to aneuploidy. PRP4-depleted cells do not arrest in mitosis after nocodazole treatment, indicating a spindle assembly checkpoint (SAC) failure. Thus, we find that PRP4 is necessary for recruitment or maintenance of the checkpoint proteins MPS1, MAD1, and MAD2 at the kinetochores. Our data clearly identify PRP4 as a previously unrecognized kinetochore component that is necessary to establish a functional SAC.


2011 ◽  
pp. 142-153
Author(s):  
Marie-Cécile Caillaud ◽  
Laetitia Paganelli ◽  
Philippe Lecomte ◽  
Laurent Deslandes ◽  
Michaël Quentin ◽  
...  

2020 ◽  
Vol 469 ◽  
pp. 11-21 ◽  
Author(s):  
Mark Bates ◽  
Fiona Furlong ◽  
Michael F. Gallagher ◽  
Cathy D. Spillane ◽  
Amanda McCann ◽  
...  

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