Dependency of the Spindle Assembly Checkpoint on Cdk1 Renders the Anaphase Transition Irreversible

• Published in: Current biology 2014-03, Vol.24 (6), p.630-637
• Main Authors: Rattani, Ahmed, Vinod, P.K., Godwin, Jonathan, Tachibana-Konwalski, Kikuë, Wolna, Magda, Malumbres, Marcos, Novák, Béla, Nasmyth, Kim
• Format: Article
• Language: English
• Subjects: Anaphase - physiology; Animals; CDC2 Protein Kinase - physiology; Cdc20 Proteins - physiology; Chromatids - physiology; Cyclin B - physiology; Female; M Phase Cell Cycle Checkpoints - physiology; Male; Mice; Mice, Knockout; Nondisjunction, Genetic - physiology; Oocytes - physiology; Phosphorylation
• ISSN: 0960-9822; 1879-0445
• DOI: 10.1016/j.cub.2014.01.033

Activation of anaphase-promoting complex/cyclosome (APC/CCdc20) by Cdc20 is delayed by the spindle assembly checkpoint (SAC). When all kinetochores come under tension, the SAC is turned off and APC/CCdc20 degrades cyclin B and securin, which activates separase [1]. The latter then cleaves cohesin holding sister chromatids together [2]. Because cohesin cleavage also destroys the tension responsible for turning off the SAC, cells must possess a mechanism to prevent SAC reactivation during anaphase, which could be conferred by a dependence of the SAC on Cdk1 [3–5]. To test this, we analyzed mouse oocytes and embryos expressing nondegradable cyclin B together with a Cdk1-resistant form of separase. After biorientation and SAC inactivation, APC/CCdc20 activates separase but the resulting loss of (some) cohesion is accompanied by SAC reactivation and APC/CCdc20 inhibition, which aborts the process of further securin degradation. Cyclin B is therefore the only APC/CCdc20 substrate whose degradation at the onset of anaphase is necessary to prevent SAC reactivation. The mutual activation of tension sensitive SAC and Cdk1 creates a bistable system that ensures complete activation of separase and total downregulation of Cdk1 when all chromosomes have bioriented. [Display omitted] •Cdk1 activity is necessary for maintaining the spindle assembly checkpoint (SAC)•SAC is reactivated during anaphase if Cdk1 activity is kept high•APC/C blocks SAC reactivation at anaphase solely by promoting cyclin B degradation•The SAC’s dependence on Cdk1 ensures that APC/C activation irreversible Rattani et al. show that Cdk1 is required for spindle assembly checkpoint (SAC) activation by unattached/tensionless chromosomes. Cdk1 inactivation through degradation of its cyclin B subunit blocks SAC reactivation during anaphase. The SAC’s dependence on Cdk1 makes separase activation irreversible.