The 'anaphase problem': how to disable the mitotic checkpoint when sisters split

Two closely connected mechanisms safeguard the fidelity of chromosome segregation in eukaryotic cells The mitotic checkpoint monitors the attachment of kinetochores to microtubules and delays anaphase onset until all sister kinetochores have become attached to opposite poles In addition an error correction mechanism destabilizes erroneous attachments that do not lead to tension at sister kinetochores Aurora B kinase the catalytic subunit of the CPC (chromosomal passenger complex) acts as a sensor and effector in both pathways In this review we focus on a poorly understood but important aspect of mitotic control what prevents the mitotic checkpoint from springing into action when sister centromeres are split and tension is suddenly lost at anaphase onset? Recent work has shown that disjunction of sister chromatids in principle engages the mitotic checkpoint and probably also the error correction mechanism with potentially catastrophic consequences for cell division Eukaryotic cells have solved this anaphase problem by disabling the mitotic checkpoint at the metaphase to anaphase transition Checkpoint inactivation is in part due to the reversal of Cdk1 (cyclin dependent kinase 1) phosphorylation of the CPC component INCENP (inner centromere protein 51115 in budding yeast) which causes the relocation of the CPC from centromeres to the spindle midzone These findings highlight principles of mitotic checkpoint control when bipolar chromosome attachment is reached in mitosis the checkpoint is satisfied but still active and responsive to loss of tension Mitotic checkpoint inactivation at anaphase onset is required to prevent checkpoint re engagement when sister chromatids split