Replicated genetic material must be partitioned equally between daughter cells during cell division. The precision with which this is accomplished depends critically on the proper functioning of the mitotic spindle. The assembly, orientation and attachment of the spindle to the kinetochores are therefore constantly monitored by a surveillance mechanism termed the SCP (spindle checkpoint). In the event of malfunction, the SCP not only prevents chromosome segregation, but also inhibits subsequent mitotic events, such as cyclin destruction (mitotic exit) and cytokinesis. This concerted action helps to maintain temporal co-ordination among mitotic events. It appears that the SCP is primarily activated by either a lack of occupancy or the absence of tension at kinetochores. Once triggered, the inhibitory circuit bifurcates, where one branch restrains the sister chromatid separation by inhibiting the E3 ligase APCCdc20 (anaphase-promoting complex activated by Cdc20) and the other impinges on the MEN (mitotic exit network). A large body of investigations has now led to the identification of the control elements, their targets and the functional coupling among them. Here we review the emerging regulatory network and discuss the remaining gaps in our understanding of this effective mechanochemical control system.

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