![]() It is crucial to resolve these issues because it is ultimately the RZZ complex that is stripped by dynein to shut down the SAC, implying that this pool of MAD1 is important for MCC generation (Howell et al, 2001 Wojcik et al, 2001 Mische et al, 2008 Sivaram et al, 2009). How exactly MAD1 is recruited to the corona and whether this pool of MAD1 can signal to the SAC are unknown. MAD1 is recruited to kinetochores via an established KNL1-BUB1 pathway and, in human cells, by an additional pathway involving the ROD/ZW10/Zwilch (RZZ) complex at the kinetochore's corona (a fibrous crescent that forms around kinetochores to aid the capture of microtubules) (Luo et al, 2018). One key unexplained aspect of the SAC concerns the kinetochore binding sites for MAD1. Removal of both MPS1 and MAD1 is essential for SAC silencing because if either one is artificially tethered to kinetochores, then the SAC fails to switch off and mitotic exit is blocked (Jelluma et al, 2010 Maldonado & Kapoor, 2011). Kinetochore–microtubule attachment extinguishes these activities because microtubules displace MPS1 from its binding site on NDC80 (Hiruma et al, 2015 Ji et al, 2015) and at the same time they provide a highway onto which dynein motors can travel to strip MAD1 away from kinetochores (Howell et al, 2001 Wojcik et al, 2001 Mische et al, 2008 Sivaram et al, 2009). Two key catalysts in this regard are MAD1, which drives the first step in MCC assembly, and MPS1, the kinase responsible for recruiting and phosphorylating MAD1 as well as other components needed for MCC assembly. This complicated inactivation process, known as SAC silencing, requires the removal of catalysts that are needed at unattached kinetochores to generate the MCC (Etemad & Kops, 2016). The generation of MCC is so efficient that every single kinetochore signalling centre must eventually be extinguished by microtubule attachment to allow the cell to exit mitosis (Rieder et al, 1995 Dick & Gerlich, 2013). The principle of the SAC is that each unattached kinetochore acts as a factory to produce an inhibitor of mitotic exit, known as the mitotic checkpoint complex or MCC (for further molecular details, see Corbett, 2017). One aspect of this regulation involves the activation of the mitotic checkpoint, otherwise known as the spindle assembly checkpoint (SAC), which blocks mitotic exit until all kinetochores have attached to microtubules. As well as attaching to microtubules, the kinetochore must also regulate this process to ensure it occurs correctly. This attachment is mediated via the kinetochore, which is a giant molecular complex assembled on chromosomes at the centromere (Musacchio & Desai, 2017). SynopsisÄuring mitosis, all duplicated chromosomes must attach correctly to microtubules so they can segregate properly when the cell divides. Therefore, this study explains how corona-MAD1 generates a robust SAC signal, and it reveals a scaffolding role for the key mitotic kinase, Cyclin B1:CDK1, which ultimately helps to inhibit its own degradation. Robustness arises because Cyclin B1:MAD1 localisation loses dependence on MPS1 kinase after the corona has been established, ensuring that corona-localised MAD1 can still be phosphorylated when MPS1 activity is low. Therefore, Cyclin B1 is the long-sought-after scaffold that links MAD1 to the corona, and this specific pool of MAD1 is needed to generate a robust SAC response. In vitro reconstitutions map the key binding interface to a few acidic residues in the N-terminal region of MAD1, and point mutations in this sequence abolish MAD1 corona localisation and weaken the SAC. Cyclin B1 localises to an expanded region of the outer kinetochore, known as the corona, where it scaffolds the spindle assembly checkpoint (SAC) machinery by binding directly to MAD1. We show here that, in addition to its kinase functions, mammalian Cyclin B also scaffolds a localised signalling pathway to help preserve genome stability. Cyclin B:CDK1 is the master kinase regulator of mitosis. ![]()
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