![]() ![]() Finally, PP1 recruitment causes dephosphorylation of the Knl1 MELTs to remove the Bub module from kinetochores. In addition, microtubule attachment by Ndc80 causes either the displacement of Mps1 from kinetochores or intra-kinetochore stretching (depicted here for illustrative purposes as extension of the Ndc80 complex we emphasize however that the molecular effector whose stretch affects SAC signaling is not known) which physically separates Mps1 from Knl1. (B) Microtubule attachments trigger the poleward transport of the Mad1-Mad2 complex by RZZ-Spindly-Dynein – this is a critical event in checkpoint silencing as preventing this transport leads to an active checkpoint despite kinetochore-microtubule attachment. Phosphorylation of BubR1 by Plk1 promotes recruitment of the PP2A-B56 phosphatase, which opposes phosphorylation of the PP1 binding motif on Knl1 by Aurora B. The RZZ complex also recruits Spindly-Dynein. Bub1, along with the RZZ complex, recruits the Mad1-Mad2 complex. (A) At unattached kinetochores Mps1, anchored onto the Ndc80 complex, phosphorylates the Knl1 MELT repeats, which recruit the Bub module (Bub1, BubR1, Bub3 and Cdc20). Kinetochores catalyze the transfer of Mad2 dynamic to Cdc20 by (1) recruiting Mad2 and Cdc20 to kinetochores, (2) positioning Cdc20 in close proximity to Mad2, and (3) unfurling Cdc20 to expose its MIM and promote the formation of the Mad2-Cdc20 complex. Mad2 is at two populations at the kinetochore: one that is stably bound to Mad1 (Mad2 scaffold) and a second that is cytosolic, transiently gets recruited to kinetochores through dimerization and becomes linked to Cdc20 (Mad2 dynamic). (C) Proposed mechanism for how unattached kinetochores catalyze formation of the Mad2-Cdc20 complex. C-Mad2 is found bound to its ligands Mad1 and Mad2, which possess Mad2-interacting motifs (MIMs). (B) Mad2 has two different conformations, Open (O) and Closed (C), which interact with each other through dimerization. ( right) During mitosis, unattached kinetochores accelerate the rate of Mad2-Cdc20 complex formation by ~200 fold. (A) ( left) Complex formation between Mad2 and Cdc20 is kinetically disfavored and subjected to disassembly by TRIP13-p31comet. ![]() Published by Elsevier Ltd.Ĭatalysis of Mad2-Cdc20 complex formation at unattached kinetochores. Here, we summarize current understanding of the mechanisms that activate and silence the SAC at kinetochores and highlight open questions for future investigation.Īneuploidy Catalysis Checkpoint Chromosome segregation Kinetochores Mitosis.Ĭopyright © 2021. However, less is understood about how SAC proteins are recruited to kinetochores in the absence of microtubule attachment, how the kinetochore catalyzes formation of the diffusible inhibitor, and how attachments silence the SAC at the kinetochore. Work from the past decade has greatly illuminated our understanding of the mechanisms by which the diffusible inhibitor is assembled and how it inhibits the APC/C. When unattached, kinetochores generate a diffusible inhibitor that blocks the activity of the anaphase-promoting complex/cyclosome (APC/C), an E3 ubiquitin ligase required for sister chromatid separation and exit from mitosis. The checkpoint senses the attachment state of kinetochores, the proteinaceous structures that assemble onto chromosomes in mitosis in order to mediate their interaction with spindle microtubules. The spindle assembly checkpoint (SAC) is a surveillance mechanism that promotes accurate chromosome segregation in mitosis. ![]()
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