Relocation of the chromosomal passenger complex prevents mitotic checkpoint engagement at anaphase.
The mitotic checkpoint monitors the attachment of kinetochores to microtubules and delays anaphase onset until all sister kinetochores have become attached to opposite poles [1, 2]. Correct bipolar attachment leads to kinetochore deformation and tension and satisfies the checkpoint [3-6]. What prevents mitotic checkpoint reactivation when sister centromeres are split and tension is lost at anaphase onset? Aurora B kinase, the catalytic subunit of the chromosomal passenger protein complex (CPC) [7], acts as a sensor at inner centromeres for the status of attachment [5, 8]. Phosphorylation of Aurora B targets at erroneously attached kinetochores elicits the correction of these attachments and the activation of the mitotic checkpoint. At anaphase, the CPC leaves the centromeres and relocates to the spindle midzone [7]. This iconic translocation might prevent the checkpoint from reengaging after anaphase onset. To test this hypothesis, we experimentally retained Aurora B and the CPC at the centromere throughout anaphase in human cells. Preventing CPC translocation caused the untimely recruitment of mitotic checkpoint proteins to kinetochores at anaphase in an Aurora B kinase activity-dependent manner. Our results suggest that the relocalization of the CPC, an evolutionarily conserved event in eukaryotes, is a key mechanism that incapacitates the mitotic checkpoint at anaphase.
Vázquez-Novelle
María Dolores
MD
Cell Division and Aneuploidy Laboratory, Cancer Research UK London Research Institute, Clare Hall Laboratories, Blanche Lane, South Mimms, Hertfordshire, UK.
Petronczki
Mark
M
D000705:Anaphase; D064107:Aurora Kinase B; D064127:Aurora Kinases; D002503:Centromere / Q000378:metabolism*; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D018386:Kinetochores / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism
D002868:Chromosomal Proteins, Non-Histone; C083767:INCENP protein, human; D029701:Saccharomyces cerevisiae Proteins; C576921:AURKB protein, human; D064107:Aurora Kinase B; D064127:Aurora Kinases; C090464:Bub1 spindle checkpoint protein; D017346:Protein Serine-Threonine Kinases; C093416:MPS1 protein, S cerevisiae