Mirchenko, L.; (2011) Mitotic checkpoint inactivation at anaphase onset. Doctoral thesis , UCL (University College London).

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Abstract

The mitotic checkpoint prevents chromosome segregation until all chromosomes have reached bi-polar orientation and come under tension on the mitotic spindle. Once this is achieved, the protease separase is activated to cleave the chromosomal cohesin complex and trigger anaphase. Cohesin cleavage releases tension between sister chromatids, however the mitotic checkpoint fails to respond to this apparent tension defect. The aim of this study was to understand why the mitotic checkpoint remains silent when sisters lose tension due to cohesin cleavage in anaphase. We showed in budding yeast that loss of sister chromatid cohesion at anaphase onset could re-activate the mitotic checkpoint. This is normally prevented by separase-dependent activation of the Cdc14 phosphatase. Cdc14 in turn downregulates the mitotic checkpoint by dephosphorylation of Sli15/INCENP, part of the conserved Aurora B kinase complex and proposed tension sensor at the kinetochores. Consequent relocation of Sli15/INCENP from centromeres to the central spindle during anaphase is a distinctive feature of the Aurora B kinase complex. Our results imply the existence of a conserved mechanism of mitotic checkpoint inactivation in anaphase. Dephosphorylation of Sli15/INCENP and its spatial separation from kinetochores prevent the checkpoint from re-engaging when tension between sister chromatids is lost in anaphase.

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