Orchestration of the spindle assembly checkpoint by CDK1‐cyclin B1

Abstract

In mitosis, the spindle assembly checkpoint (SAC) monitors the formation of microtubule‐kinetochore attachments during capture of chromosomes by the mitotic spindle. Spindle assembly is complete once there are no longer any unattached kinetochores. Here, we will discuss the mechanism and key components of spindle checkpoint signalling. Unattached kinetochores bind the principal spindle checkpoint kinase monopolar spindle 1 (MPS1). MPS1 triggers the recruitment of other spindle checkpoint proteins and the formation of a soluble inhibitor of anaphase, thus preventing exit from mitosis. On microtubule attachment, kinetochores become checkpoint silent due to the actions of PP2A‐B56 and PP1. This SAC responsive period has to be coordinated with mitotic spindle formation to ensure timely mitotic exit and accurate chromosome segregation. We focus on the molecular mechanisms by which the SAC permissive state is created, describing a central role for CDK1‐cyclin B1 and its counteracting phosphatase PP2A‐B55. Furthermore, we discuss how CDK1‐cyclin B1, through its interaction with MAD1, acts as an integral component of the SAC, and actively orchestrates checkpoint signalling and thus contributes to the faithful execution of mitosis.

Depletion of Trichoplein (TpMs) Causes Chromosome Mis-Segregation, DNA Damage and Chromosome Instability in Cancer Cells

“…Impaired Mad2 levels are known to cause premature activation of the APC/C, which usually allows the proper anaphase onset. It is conceivable that the decreased Mad2 level in TpMs-depleted cells fails to inhibit APC/C activity causing the anaphase to occur at earlier times than in the typical cell cycle progressing [33]. Moreover, we reported the early degradation of Cyclin B1 in TpMs-deprived cells.…”

PP1 promotes cyclin B destruction and the metaphase-anaphase transition by dephosphorylating CDC20

“…Whether this is a direct effect of phosphorylation promoting incorporation of CDC20 into MCC, or an indirect effect of non-phosphorylated CDC20 preferentially binding to APC/C and thus changing the pool of CDC20 available for MCC formation, is unclear. Completing this regulatory circuit, CDK1-cyclin B1 directly aids the production of MCC by promoting the activation and recruitment of the checkpoint kinase, MPS1, to kinetochores (Alfonso-Perez et al, 2019;Hayward et al, 2019a;Hayward et al, 2019b;Morin et al, 2012;Vazquez-Novelle et al, 2014). This CDK1-cyclin B dependent cycle of MCC production and inhibition of APC/C thus prevents entry into anaphase until stable microtubule-kinetochore attachment has been achieved at all kinetochores.…”

A Peak of H3T3 Phosphorylation Occurs in Synchrony with Mitosis in Sea Urchin Early Embryos

“…The Cyclin B/CDK1 (Cyclin Dependent Kinase 1) complex is the key factor orchestrating these different processes, acting upstream of a cascade of post-translational regulatory events [8]. For instance, the contribution of this complex is essential for the activation of the multiple kinases and phosphatases participating during kinetochore assembly and chromosome segregation [9,10]. However, despite the fact that Cyclins were first described in sea urchin embryos [11], little is known in these animals about the identity of the Cyclin B/CDK1 targets, especially at the chromatin level.…”