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.
Highlights
Mitotic arrest deficient, Murray lab) were the founding members of the spindle assembly checkpoint - abbreviated to SAC - the signalling network that halts anaphase entry when spindle defects are detected
In contrast to other genes required for spindle pole body duplication, yeast cells in which Monopolar Spindle 1 (MPS1) had been inactivated progressed through the cell cycle despite their inability to form a bipolar mitotic spindle [38, 39] similar to the behaviour of the mitotic checkpoint mutants identified by Hoyt and Murray
Mitotic phosphorylations are counteracted by phosphoprotein phosphatases So far, we have considered the generation of phosphorylations by CDK1-cyclin B1 and the functional consequences thereof
Summary
Mitotic arrest deficient, Murray lab) were the founding members of the spindle assembly checkpoint - abbreviated to SAC - the signalling network that halts anaphase entry when spindle defects are detected. A further demonstration of the close relationship of CDK1-cyclin B1 with its substrates in the mitotic checkpoint signalling cascade is the finding that cyclin B1 itself is localised to unattached kinetochores and displaced from these upon microtubule binding, just like a bona fide SAC protein [117119] (Figure 4). Comparison of PP2A-B55 to other phosphatases modulating the SAC While CDK1 and PP2A-B55 are important for demarcating the spindle checkpoint permissive period, within the SAC licensed period a large number of phosphorylations are deposited by MPS1 and have to be dynamically controlled and removed before the metaphase-to-anaphase transition to enable SAC silencing and mitotic exit.
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