Abstract
In eukaryotic cell division, the Spindle Assembly Checkpoint (SAC) plays a key regulatory role by monitoring the status of chromosome-microtubule attachments and allowing chromosome segregation only after all chromosomes are properly attached to spindle microtubules. While the identities of SAC components have been known, in some cases, for over two decades, the molecular mechanisms of the SAC have remained mostly mysterious until very recently. In the past few years, advances in biochemical reconstitution, structural biology, and bioinformatics have fueled an explosion in the molecular understanding of the SAC. This chapter seeks to synthesize these recent advances and place them in a biological context, in order to explain the mechanisms of SAC activation and silencing at a molecular level.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Alfieri C, Chang L, Zhang Z et al (2016) Molecular basis of APC/C regulation by the spindle assembly checkpoint. Nature 536:431–436. doi:10.1038/nature19083
Aravamudhan P, Goldfarb AA, Joglekar AP (2015) The kinetochore encodes a mechanical switch to disrupt spindle assembly checkpoint signalling. Nat Cell Biol 17:868–879. doi:10.1038/ncb3179
Aravind L, Koonin EV (1998) The HORMA domain: a common structural denominator in mitotic checkpoints, chromosome synapsis and DNA repair. Trends Biochem Sci 23:284–286
Barford D (2015) Understanding the structural basis for controlling chromosome division. Philos Trans A Math Phys Eng Sci 373:20130392. doi:10.1098/rsta.2013.0392
Barisic M, Geley S (2011) Spindly switch controls anaphase: spindly and RZZ functions in chromosome attachment and mitotic checkpoint control. Cell Cycle 10:449–456. doi:10.4161/cc.10.3.14759
Barisic M, Sohm B, Mikolcevic P et al (2010) Spindly/CCDC99 is required for efficient chromosome congression and mitotic checkpoint regulation. Mol Biol Cell 21:1968–1981. doi:10.1091/mbc.E09-04-0356
Borner GV, Barot A, Kleckner N (2008) Yeast Pch2 promotes domainal axis organization, timely recombination progression, and arrest of defective recombinosomes during meiosis. Proc Natl Acad Sci U S A 105:3327–3332. doi:10.1073/pnas.0711864105
Brown NG, VanderLinden R, Watson ER et al (2015) RING E3 mechanism for ubiquitin ligation to a disordered substrate visualized for human anaphase-promoting complex. Proc Natl Acad Sci U S A 112:5272–5279. doi:10.1073/pnas.1504161112
Brown NG, VanderLinden R, Watson ER et al (2016) Dual RING E3 architectures regulate multiubiquitination and ubiquitin chain elongation by APC/C. Cell 165:1440–1453. doi:10.1016/j.cell.2016.05.037
Buffin E, Lefebvre C, Huang J et al (2005) Recruitment of Mad2 to the kinetochore requires the Rod/Zw10 complex. Curr Biol 15:856–861. doi:10.1016/j.cub.2005.03.052
Burton JL, Xiong Y, Solomon MJ (2011) Mechanisms of pseudosubstrate inhibition of the anaphase promoting complex by Acm1. EMBO J 30:1818–1829. doi:10.1038/emboj.2011.90
Buschhorn BA, Petzold G, Galova M et al (2011) Substrate binding on the APC/C occurs between the coactivator Cdh1 and the processivity factor Doc1. Nat Struct Mol Biol 18:6–13. doi:10.1038/nsmb.1979
Caldas GV, Lynch TR, Anderson R et al (2015) The RZZ complex requires the N-terminus of KNL1 to mediate optimal Mad1 kinetochore localization in human cells. Open Biol 5:150160. doi:10.1098/rsob.150160
Carmena M, Wheelock M, Funabiki H, Earnshaw WC (2012) The chromosomal passenger complex (CPC): from easy rider to the godfather of mitosis. Nat Rev Mol Cell Biol 13:789–803. doi:10.1038/nrm3474
Chan YW, Fava LL, Uldschmid A et al (2009) Mitotic control of kinetochore-associated dynein and spindle orientation by human Spindly. J Cell Biol 185:859–874. doi:10.1083/jcb.200812167
Chang L, Barford D (2014) Insights into the anaphase-promoting complex: a molecular machine that regulates mitosis. Curr Opin Struct Biol 29:1–9. doi:10.1016/j.sbi.2014.08.003
Chang L, Zhang Z, Yang J et al (2014) Molecular architecture and mechanism of the anaphase-promoting complex. Nature 513:388–393. doi:10.1038/nature13543
Chang L, Zhang Z, Yang J et al (2015) Atomic structure of the APC/C and its mechanism of protein ubiquitination. Nature 522:450–454. doi:10.1038/nature14471
Chao WCH, Kulkarni K, Zhang Z et al (2012) Structure of the mitotic checkpoint complex. Nature 484:208–213. doi:10.1038/nature10896
Cheeseman IM, Niessen S, Anderson S et al (2004) A conserved protein network controls assembly of the outer kinetochore and its ability to sustain tension. Genes Dev 18:2255–2268. doi:10.1101/gad.1234104
Cheeseman IM, Chappie JS, Wilson-Kubalek EM, Desai A (2006) The conserved KMN network constitutes the core microtubule-binding site of the kinetochore. Cell 127:983–997. doi:10.1016/j.cell.2006.09.039
Ciferri C, Pasqualato S, Screpanti E et al (2008) Implications for kinetochore-microtubule attachment from the structure of an engineered Ndc80 complex. Cell 133:427–439. doi:10.1016/j.cell.2008.03.020
Ciosk R, Zachariae W, Michaelis C et al (1998) An ESP1/PDS1 complex regulates loss of sister chromatid cohesion at the metaphase to anaphase transition in yeast. Cell 93:1067–1076
Cohen-Fix O, Peters JM, Kirschner MW, Koshland D (1996) Anaphase initiation in Saccharomyces cerevisiae is controlled by the APC-dependent degradation of the anaphase inhibitor Pds1p. Genes Dev 10:3081–3093
da Fonseca PCA, Kong EH, Zhang Z et al (2011) Structures of APC/C(Cdh1) with substrates identify Cdh1 and Apc10 as the D-box co-receptor. Nature 470:274–278. doi:10.1038/nature09625
Davey NE, Morgan DO (2016) Building a regulatory network with short linear sequence motifs: lessons from the degrons of the anaphase-promoting complex. Mol Cell 64:12–23. doi:10.1016/j.molcel.2016.09.006
de Antoni A, Pearson CG, Cimini D et al (2005) The Mad1/Mad2 complex as a template for Mad2 activation in the spindle assembly checkpoint. Curr Biol 15:214–225. doi:10.1016/j.cub.2005.01.038
Desai A, Rybina S, Müller-Reichert T et al (2003) KNL-1 directs assembly of the microtubule-binding interface of the kinetochore in C. elegans. Genes Dev 17:2421–2435. doi:10.1101/gad.1126303
Di Fiore B, Davey NE, Hagting A et al (2015) The ABBA motif binds APC/C activators and is shared by APC/C substrates and regulators. Dev Cell 32:358–372. doi:10.1016/j.devcel.2015.01.003
Di Fiore B, Wurzenberger C, Davey NE, Pines J (2016) The mitotic checkpoint complex requires an evolutionary conserved cassette to bind and inhibit active APC/C. Mol Cell 64:1144–1153. doi:10.1016/j.molcel.2016.11.006
Diaz-Martinez LA, Tian W, Li B et al (2015) The Cdc20-binding Phe box of the spindle checkpoint protein BubR1 maintains the mitotic checkpoint complex during mitosis. J Biol Chem 290:2431–2443. doi:10.1074/jbc.M114.616490
Dou Z, Liu X, Wang W et al (2015) Dynamic localization of Mps1 kinase to kinetochores is essential for accurate spindle microtubule attachment. Proc Natl Acad Sci U S A 112:E4546–E4555. doi:10.1073/pnas.1508791112
Espert A, Uluocak P, Bastos RN et al (2014) PP2A-B56 opposes Mps1 phosphorylation of Knl1 and thereby promotes spindle assembly checkpoint silencing. J Cell Biol 206:833–842. doi:10.1083/jcb.201406109
Etemad B, Kops GJPL (2016) Attachment issues: kinetochore transformations and spindle checkpoint silencing. Curr Opin Cell Biol 39:101–108. doi:10.1016/j.ceb.2016.02.016
Eytan E, Wang K, Miniowitz-Shemtov S et al (2014) Disassembly of mitotic checkpoint complexes by the joint action of the AAA-ATPase TRIP13 and p31(comet). Proc Natl Acad Sci U S A 111:12019–12024. doi:10.1073/pnas.1412901111
Faesen AC, Thanasoula M, Maffini S et al (2017) In vitro reconstitution of spindle assembly checkpoint signaling identifies the determinants of catalytic assembly of the mitotic checkpoint complex. Nature 542:498–502. doi:10.1038/nature21384
Fang G (2002) Checkpoint protein BubR1 acts synergistically with Mad2 to inhibit anaphase-promoting complex. Mol Biol Cell 13:755–766. doi:10.1091/mbc.01-09-0437
Fang G, Yu H, Kirschner MW (1998) The checkpoint protein MAD2 and the mitotic regulator CDC20 form a ternary complex with the anaphase-promoting complex to control anaphase initiation. Genes Dev 12:1871–1883
Foe IT, Foster SA, Cheung SK et al (2011) Ubiquitination of Cdc20 by the APC occurs through an intramolecular mechanism. Curr Biol 21:1870–1877. doi:10.1016/j.cub.2011.09.051
Foley EA, Kapoor TM (2013) Microtubule attachment and spindle assembly checkpoint signalling at the kinetochore. Nat Rev Mol Cell Biol 14:25–37. doi:10.1038/nrm3494
Foster SA, Morgan DO (2012) The APC/C subunit Mnd2/Apc15 promotes Cdc20 autoubiquitination and spindle assembly checkpoint inactivation. Mol Cell 47:921–932. doi:10.1016/j.molcel.2012.07.031
Gassmann R, Essex A, Hu J-S et al (2008) A new mechanism controlling kinetochore-microtubule interactions revealed by comparison of two dynein-targeting components: SPDL-1 and the Rod/Zwilch/Zw10 complex. Genes Dev 22:2385–2399. doi:10.1101/gad.1687508
Gassmann R, Holland AJ, Varma D et al (2010) Removal of spindly from microtubule-attached kinetochores controls spindle checkpoint silencing in human cells. Genes Dev 24:957–971. doi:10.1101/gad.1886810
Ge S, Skaar JR, Pagano M (2009) APC/C- and Mad2-mediated degradation of Cdc20 during spindle checkpoint activation. Cell Cycle 8:167–171. doi:10.4161/cc.8.1.7606
Glotzer M, Murray AW, Kirschner MW (1991) Cyclin is degraded by the ubiquitin pathway. Nature 349:132–138. doi:10.1038/349132a0
Golan A, Yudkovsky Y, Hershko A (2002) The cyclin-ubiquitin ligase activity of cyclosome/APC is jointly activated by protein kinases Cdk1-cyclin B and Plk. J Biol Chem 277:15552–15557. doi:10.1074/jbc.M111476200
Habu T, Kim SH, Weinstein J, Matsumoto T (2002) Identification of a MAD2-binding protein, CMT2, and its role in mitosis. EMBO J 21:6419–6428
Han JS, Holland AJ, Fachinetti D et al (2013) Catalytic assembly of the mitotic checkpoint inhibitor BubR1-Cdc20 by a Mad2-induced functional switch in Cdc20. Mol Cell 51:92–104. doi:10.1016/j.molcel.2013.05.019
Hara M, Özkan E, Sun H et al (2015) Structure of an intermediate conformer of the spindle checkpoint protein Mad2. Proc Natl Acad Sci U S A 112:11252–11257. doi:10.1073/pnas.1512197112
Hardwick KG, Johnston RC, Smith DL, Murray AW (2000) MAD3 encodes a novel component of the spindle checkpoint which interacts with Bub3p, Cdc20p, and Mad2p. J Cell Biol 148:871–882. doi:10.1083/jcb.148.5.871
Hardwick KG, Weiss E, Luca FC et al (1996) Activation of the budding yeast spindle assembly checkpoint without mitotic spindle disruption. Science 273:953–956
He J, Chao WCH, Zhang Z et al (2013) Insights into degron recognition by APC/C coactivators from the structure of an Acm1-Cdh1 complex. Mol Cell 50:649–660. doi:10.1016/j.molcel.2013.04.024
Hendrickx A, Beullens M, Ceulemans H et al (2009) Docking motif-guided mapping of the interactome of protein phosphatase-1. Chem Biol 16:365–371. doi:10.1016/j.chembiol.2009.02.012
Herzog F, Primorac I, Dube P et al (2009) Structure of the anaphase-promoting complex/cyclosome interacting with a mitotic checkpoint complex. Science 323:1477–1481. doi:10.1126/science.1163300
Hiruma Y, Sacristan C, Pachis ST et al (2015) CELL DIVISION CYCLE. Competition between MPS1 and microtubules at kinetochores regulates spindle checkpoint signaling. Science 348:1264–1267. doi:10.1126/science.aaa4055
Howell BJ, McEwen BF, Canman JC et al (2001) Cytoplasmic dynein/dynactin drives kinetochore protein transport to the spindle poles and has a role in mitotic spindle checkpoint inactivation. J Cell Biol 155:1159–1172. doi:10.1083/jcb.200105093
Howell BJ, Moree B, Farrar EM et al (2004) Spindle checkpoint protein dynamics at kinetochores in living cells. Curr Biol 14:953–964. doi:10.1016/j.cub.2004.05.053
Hoyt MA, Totis L, Roberts BT (1991) S. cerevisiae genes required for cell cycle arrest in response to loss of microtubule function. Cell 66:507–517
Hwang LH, Lau LF, Smith DL et al (1998) Budding yeast Cdc20: a target of the spindle checkpoint. Science 279:1041–1044
Izawa D, Pines J (2012) Mad2 and the APC/C compete for the same site on Cdc20 to ensure proper chromosome segregation. J Cell Biol 199:27–37. doi:10.1083/jcb.201205170
Izawa D, Pines J (2014) The mitotic checkpoint complex binds a second CDC20 to inhibit active APC/C. Nature. doi:10.1038/nature13911
Jaspersen SL, Charles JF, Morgan DO (1999) Inhibitory phosphorylation of the APC regulator Hct1 is controlled by the kinase Cdc28 and the phosphatase Cdc14. Curr Biol 9:227–236
Ji Z, Gao H, Yu H (2015) Cell division cycle. Kinetochore attachment sensed by competitive Mps1 and microtubule binding to Ndc80C. Science 348:1260–1264. doi:10.1126/science.aaa4029
Ji Z, Gao H, Jia L et al (2017) A sequential multi-target Mps1 phosphorylation cascade promotes spindle checkpoint signaling. Elife 6:e22513. doi:10.7554/eLife.22513
Kallio M, Weinstein J, Daum JR et al (1998) Mammalian p55CDC mediates association of the spindle checkpoint protein Mad2 with the cyclosome/anaphase-promoting complex, and is involved in regulating anaphase onset and late mitotic events. J Cell Biol 141:1393–1406
Kamenz J, Hauf S (2016) Time to split up: dynamics of chromosome separation. Trends Cell Biol. doi:10.1016/j.tcb.2016.07.008
Karess R (2005) Rod-Zw10-Zwilch: a key player in the spindle checkpoint. Trends Cell Biol 15:386–392. doi:10.1016/j.tcb.2005.05.003
Kim SH, Lin DP, Matsumoto S et al (1998) Fission yeast Slp1: an effector of the Mad2-dependent spindle checkpoint. Science 279:1045–1047
King RW, Peters JM, Tugendreich S et al (1995) A 20S complex containing CDC27 and CDC16 catalyzes the mitosis-specific conjugation of ubiquitin to cyclin B. Cell 81:279–288
King EMJ, van der Sar SJA, Hardwick KG (2007) Mad3 KEN boxes mediate both Cdc20 and Mad3 turnover, and are critical for the spindle checkpoint. PLoS ONE 2:e342. doi:10.1371/journal.pone.0000342
Kops GJPL, Kim Y, Weaver BAA et al (2005) ZW10 links mitotic checkpoint signaling to the structural kinetochore. J Cell Biol 169:49–60. doi:10.1083/jcb.200411118
Kraft C, Herzog F, Gieffers C et al (2003) Mitotic regulation of the human anaphase-promoting complex by phosphorylation. EMBO J 22:6598–6609. doi:10.1093/emboj/cdg627
Kramer ER, Scheuringer N, Podtelejnikov AV et al (2000) Mitotic regulation of the APC activator proteins CDC20 and CDH1. Mol Biol Cell 11:1555–1569
Krenn V, Musacchio A (2015) The Aurora B kinase in chromosome bi-orientation and spindle checkpoint signaling. Front Oncol 5:225. doi:10.3389/fonc.2015.00225
Krenn V, Overlack K, Primorac I et al (2014) KI motifs of human Knl1 enhance assembly of comprehensive spindle checkpoint complexes around MELT repeats. Curr Biol 24:29–39. doi:10.1016/j.cub.2013.11.046
Kulukian A, Han JS, Cleveland DW (2009) Unattached kinetochores catalyze production of an anaphase inhibitor that requires a Mad2 template to prime Cdc20 for BubR1 binding. Dev Cell 16:105–117. doi:10.1016/j.devcel.2008.11.005
Labit H, Fujimitsu K, Bayin NS et al (2012) Dephosphorylation of Cdc20 is required for its C-box-dependent activation of the APC/C. EMBO J 31:3351–3362. doi:10.1038/emboj.2012.168
Lahav-Baratz S, Sudakin V, Ruderman JV, Hershko A (1995) Reversible phosphorylation controls the activity of cyclosome-associated cyclin-ubiquitin ligase. Proc Natl Acad Sci U S A 92:9303–9307
Lampson MA, Cheeseman IM (2011) Sensing centromere tension: Aurora B and the regulation of kinetochore function. Trends Cell Biol 21:133–140. doi:10.1016/j.tcb.2010.10.007
Lan W, Cleveland DW (2010) A chemical tool box defines mitotic and interphase roles for Mps1 kinase. J Cell Biol 190:21–24. doi:10.1083/jcb.201006080
Lara-Gonzalez P, Westhorpe FG, Taylor SS (2012) The Spindle Assembly Checkpoint. Curr Biol 22:R966–R980. doi:10.1016/j.cub.2012.10.006
Larsen NA, Al-Bassam J, Wei RR, Harrison SC (2007) Structural analysis of Bub3 interactions in the mitotic spindle checkpoint. Proc Natl Acad Sci U S A 104:1201–1206. doi:10.1073/pnas.0610358104
Li R, Murray AW (1991) Feedback control of mitosis in budding yeast. Cell 66:519–531
Li Y, Gorbea C, Mahaffey D et al (1997) MAD2 associates with the cyclosome/anaphase-promoting complex and inhibits its activity. Proc Natl Acad Sci U S A 94:12431–12436
Lischetti T, Zhang G, Sedgwick GG et al (2014) The internal Cdc20 binding site in BubR1 facilitates both spindle assembly checkpoint signalling and silencing. Nat Commun 5:5563. doi:10.1038/ncomms6563
Liu X, Winey M (2012) The MPS1 family of protein kinases. Annu Rev Biochem 81:561–585. doi:10.1146/annurev-biochem-061611-090435
Liu D, Vleugel M, Backer CB et al (2010) Regulated targeting of protein phosphatase 1 to the outer kinetochore by KNL1 opposes Aurora B kinase. J Cell Biol 188:809–820. doi:10.1083/jcb.201001006
London N, Biggins S (2014) Mad1 kinetochore recruitment by Mps1-mediated phosphorylation of Bub1 signals the spindle checkpoint. Genes Dev 28:140–152. doi:10.1101/gad.233700.113
London N, Ceto S, Ranish JA, Biggins S (2012) Phosphoregulation of Spc105 by Mps1 and PP1 regulates Bub1 localization to kinetochores. Curr Biol 22:900–906. doi:10.1016/j.cub.2012.03.052
Lukas C, Sørensen CS, Kramer E et al (1999) Accumulation of cyclin B1 requires E2F and cyclin-A-dependent rearrangement of the anaphase-promoting complex. Nature 401:815–818. doi:10.1038/44611
Luo X, Yu H (2008) Protein metamorphosis: the two-state behavior of Mad2. Structure 16:1616–1625. doi:10.1016/j.str.2008.10.002
Luo X, Fang G, Coldiron M et al (2000) Structure of the Mad2 spindle assembly checkpoint protein and its interaction with Cdc20. Nat Struct Biol 7:224–229. doi:10.1038/73338
Luo X, Tang Z, Rizo J, Yu H (2002) The Mad2 spindle checkpoint protein undergoes similar major conformational changes upon binding to either Mad1 or Cdc20. Mol Cell 9:59–71
Luo X, Tang Z, Xia G et al (2004) The Mad2 spindle checkpoint protein has two distinct natively folded states. Nat Struct Mol Biol 11:338–345. doi:10.1038/nsmb748
Ma HT, Poon RYC (2016) TRIP13 regulates both the activation and inactivation of the spindle-assembly checkpoint. Cell Reports 14:1086–1099. doi:10.1016/j.celrep.2016.01.001
Mansfeld J, Collin P, Collins MO et al (2011) APC15 drives the turnover of MCC-CDC20 to make the spindle assembly checkpoint responsive to kinetochore attachment. Nat Cell Biol 13:1234–1243. doi:10.1038/ncb2347
Mapelli M, Musacchio A (2007) MAD contortions: conformational dimerization boosts spindle checkpoint signaling. Curr Opin Struct Biol 17:716–725. doi:10.1016/j.sbi.2007.08.011
Mapelli M, Massimiliano L, Santaguida S, Musacchio A (2007) The Mad2 conformational dimer: structure and implications for the spindle assembly checkpoint. Cell 131:730–743. doi:10.1016/j.cell.2007.08.049
Martin-Lluesma S, Stucke VM, Nigg EA (2002) Role of Hec1 in spindle checkpoint signaling and kinetochore recruitment of Mad1/Mad2. Science 297:2267–2270. doi:10.1126/science.1075596
Matyskiela ME, Morgan DO (2009) Analysis of activator-binding sites on the APC/C supports a cooperative substrate-binding mechanism. Mol Cell 34:68–80. doi:10.1016/j.molcel.2009.02.027
Meadows JC, Shepperd LA, Vanoosthuyse V et al (2011) Spindle checkpoint silencing requires association of PP1 to both Spc7 and kinesin-8 motors. Dev Cell 20:739–750. doi:10.1016/j.devcel.2011.05.008
Miniowitz-Shemtov S, Eytan E, Kaisari S et al (2015) Mode of interaction of TRIP13 AAA-ATPase with the Mad2-binding protein p31comet and with mitotic checkpoint complexes. Proc Natl Acad Sci U S A 112:11536–11540. doi:10.1073/pnas.1515358112
Morgan DO (1997) Cyclin-dependent kinases: engines, clocks, and microprocessors. Annu Rev Cell Dev Biol 13:261–291. doi:10.1146/annurev.cellbio.13.1.261
Moyle MW, Kim T, Hattersley N et al (2014) A Bub1-Mad1 interaction targets the Mad1-Mad2 complex to unattached kinetochores to initiate the spindle checkpoint. J Cell Biol 204:647–657. doi:10.1083/jcb.201311015
Murray AW, Solomon MJ, Kirschner MW (1989) The role of cyclin synthesis and degradation in the control of maturation promoting factor activity. Nature 339:280–286. doi:10.1038/339280a0
Musacchio A (2015) The molecular biology of spindle assembly checkpoint signaling dynamics. Curr Biol 25:R1002–R1018. doi:10.1016/j.cub.2015.08.051
Musacchio A, Salmon ED (2007) The spindle-assembly checkpoint in space and time. Nat Rev Mol Cell Biol 8:379–393. doi:10.1038/nrm2163
Nagpal H, Fukagawa T (2016) Kinetochore assembly and function through the cell cycle. Chromosoma 125:645–659. doi:10.1007/s00412-016-0608-3
Nekrasov VS, Smith MA, Peak-Chew S, Kilmartin JV (2003) Interactions between centromere complexes in Saccharomyces cerevisiae. Mol Biol Cell 14:4931–4946. doi:10.1091/mbc.E03-06-0419
Nelson CR, Hwang T, Chen P-H, Bhalla N (2015) TRIP13/PCH-2 promotes Mad2 localization to unattached kinetochores in the spindle checkpoint response. J Cell Biol 211:503–516. doi:10.1083/jcb.201505114
Nezi L, Rancati G, de Antoni A et al (2006) Accumulation of Mad2-Cdc20 complex during spindle checkpoint activation requires binding of open and closed conformers of Mad2 in Saccharomyces cerevisiae. J Cell Biol 174:39–51. doi:10.1083/jcb.200602109
Nijenhuis W, von Castelmur E, Littler D et al (2013) A TPR domain-containing N-terminal module of MPS1 is required for its kinetochore localization by Aurora B. J Cell Biol 201:217–231. doi:10.1083/jcb.201210033
Nijenhuis W, Vallardi G, Teixeira A et al (2014) Negative feedback at kinetochores underlies a responsive spindle checkpoint signal. Nat Cell Biol 16:1257–1264. doi:10.1038/ncb3065
Nilsson J, Yekezare M, Minshull J, Pines J (2008) The APC/C maintains the spindle assembly checkpoint by targeting Cdc20 for destruction. Nat Cell Biol 10:1411–1420. doi:10.1038/ncb1799
Overlack K, Primorac I, Vleugel M et al (2015) A molecular basis for the differential roles of Bub1 and BubR1 in the spindle assembly checkpoint. Elife 4:e05269. doi:10.7554/eLife.05269
Pan J, Chen R-H (2004) Spindle checkpoint regulates Cdc20p stability in Saccharomyces cerevisiae. Genes Dev 18:1439–1451. doi:10.1101/gad.1184204
Pesenti ME, Weir JR, Musacchio A (2016) Progress in the structural and functional characterization of kinetochores. Curr Opin Struct Biol 37:152–163. doi:10.1016/j.sbi.2016.03.003
Pfleger CM, Kirschner MW (2000) The KEN box: an APC recognition signal distinct from the D box targeted by Cdh1. Genes Dev 14:655–665
Primorac I, Musacchio A (2013) Panta rhei: the APC/C at steady state. J Cell Biol 201:177–189. doi:10.1083/jcb.201301130
Primorac I, Weir JR, Chiroli E et al (2013) Bub3 reads phosphorylated MELT repeats to promote spindle assembly checkpoint signaling. Elife 2:e01030. doi:10.7554/eLife.01030
Qiao R, Weissmann F, Yamaguchi M et al (2016) Mechanism of APC/CCDC20 activation by mitotic phosphorylation. Proc Natl Acad Sci U S A 113:E2570–E2578. doi:10.1073/pnas.1604929113
Reddy SK, Rape M, Margansky WA, Kirschner MW (2007) Ubiquitination by the anaphase-promoting complex drives spindle checkpoint inactivation. Nature 446:921–925. doi:10.1038/nature05734
Reis A, Levasseur M, Chang H-Y et al (2006) The CRY box: a second APCcdh1-dependent degron in mammalian cdc20. EMBO Rep 7:1040–1045. doi:10.1038/sj.embor.7400772
Rieder CL, Cole RW, Khodjakov A, Sluder G (1995) The checkpoint delaying anaphase in response to chromosome monoorientation is mediated by an inhibitory signal produced by unattached kinetochores. J Cell Biol 130:941–948
Rosenberg JS, Cross FR, Funabiki H (2011) KNL1/Spc105 recruits PP1 to silence the spindle assembly checkpoint. Curr Biol 21:942–947. doi:10.1016/j.cub.2011.04.011
San-Segundo PA, Roeder GS (1999) Pch2 links chromatin silencing to meiotic checkpoint control. Cell 97:313–324
Schwab M, Neutzner M, Möcker D, Seufert W (2001) Yeast Hct1 recognizes the mitotic cyclin Clb2 and other substrates of the ubiquitin ligase APC. EMBO J 20:5165–5175. doi:10.1093/emboj/20.18.5165
Sczaniecka M, Feoktistova A, May KM et al (2008) The spindle checkpoint functions of Mad3 and Mad2 depend on a Mad3 KEN box-mediated interaction with Cdc20-anaphase-promoting complex (APC/C). J Biol Chem 283:23039–23047. doi:10.1074/jbc.M803594200
Shah JV, Botvinick E, Bonday Z et al (2004) Dynamics of centromere and kinetochore proteins; implications for checkpoint signaling and silencing. Curr Biol 14:942–952. doi:10.1016/j.cub.2004.05.046
Shepperd LA, Meadows JC, Sochaj AM et al (2012) Phosphodependent recruitment of Bub1 and Bub3 to Spc7/KNL1 by Mph1 kinase maintains the spindle checkpoint. Curr Biol 22:891–899. doi:10.1016/j.cub.2012.03.051
Shirayama M, Toth A, Gálová M, Nasmyth K (1999) APC(Cdc20) promotes exit from mitosis by destroying the anaphase inhibitor Pds1 and cyclin Clb5. Nature 402:203–207. doi:10.1038/46080
Shteinberg M, Protopopov Y, Listovsky T et al (1999) Phosphorylation of the cyclosome is required for its stimulation by Fizzy/cdc20. Biochem Biophys Res Commun 260:193–198. doi:10.1006/bbrc.1999.0884
Silió V, McAinsh AD, Millar JB (2015) KNL1-Bubs and RZZ provide two separable pathways for checkpoint activation at human kinetochores. Dev Cell 35:600–613. doi:10.1016/j.devcel.2015.11.012
Simonetta M, Manzoni R, Mosca R et al (2009) The influence of catalysis on mad2 activation dynamics. PLoS Biol 7:e10. doi:10.1371/journal.pbio.1000010
Sironi L, Mapelli M, Knapp S et al (2002) Crystal structure of the tetrameric Mad1-Mad2 core complex: implications of a “safety belt” binding mechanism for the spindle checkpoint. EMBO J 21:2496–2506. doi:10.1093/emboj/21.10.2496
Starr DA, Williams BC, Hays TS, Goldberg ML (1998) ZW10 helps recruit dynactin and dynein to the kinetochore. J Cell Biol 142:763–774
Sudakin V, Chan GK, Yen TJ (2001) Checkpoint inhibition of the APC/C in HeLa cells is mediated by a complex of BUBR1, BUB3, CDC20, and MAD2. J Cell Biol 154:925–936. doi:10.1083/jcb.200102093
Sudakin V, Ganoth D, Dahan A et al (1995) The cyclosome, a large complex containing cyclin-selective ubiquitin ligase activity, targets cyclins for destruction at the end of mitosis. Mol Biol Cell 6:185–197
Suijkerbuijk SJE, van Dam TJP, Karagöz GE et al (2012a) The vertebrate mitotic checkpoint protein BUBR1 is an unusual pseudokinase. Dev Cell 22:1321–1329. doi:10.1016/j.devcel.2012.03.009
Suijkerbuijk SJE, Vleugel M, Teixeira A, Kops GJPL (2012b) Integration of kinase and phosphatase activities by BUBR1 ensures formation of stable kinetochore-microtubule attachments. Dev Cell 23:745–755. doi:10.1016/j.devcel.2012.09.005
Tang Z, Bharadwaj R, Li B, Yu H (2001) Mad2-Independent inhibition of APCCdc20 by the mitotic checkpoint protein BubR1. Dev Cell 1:227–237
Taylor SS, Ha E, McKeon F (1998) The human homologue of Bub3 is required for kinetochore localization of Bub1 and a Mad3/Bub1-related protein kinase. J Cell Biol 142:1–11
Teichner A, Eytan E, Sitry-Shevah D et al (2011) p31comet Promotes disassembly of the mitotic checkpoint complex in an ATP-dependent process. Proc Natl Acad Sci U S A 108:3187–3192. doi:10.1073/pnas.1100023108
Thornton BR, Ng TM, Matyskiela ME et al (2006) An architectural map of the anaphase-promoting complex. Genes Dev 20:449–460. doi:10.1101/gad.1396906
Tipton AR, Wang K, Link L et al (2011) BUBR1 and closed MAD2 (C-MAD2) interact directly to assemble a functional mitotic checkpoint complex. J Biol Chem 286:21173–21179. doi:10.1074/jbc.M111.238543
Tipton AR, Wang K, Oladimeji P et al (2012) Identification of novel mitosis regulators through data mining with human centromere/kinetochore proteins as group queries. BMC Cell Biol 13:15. doi:10.1186/1471-2121-13-15
Uzunova K, Dye BT, Schutz H et al (2012) APC15 mediates CDC20 autoubiquitylation by APC/C(MCC) and disassembly of the mitotic checkpoint complex. Nat Struct Mol Biol 19:1116–1123. doi:10.1038/nsmb.2412
Vader G (2015) Pch2(TRIP13): controlling cell division through regulation of HORMA domains. Chromosoma 124:333–339. doi:10.1007/s00412-015-0516-y
van der Horst A, Lens SMA (2014) Cell division: control of the chromosomal passenger complex in time and space. Chromosoma 123:25–42. doi:10.1007/s00412-013-0437-6
Varma D, Salmon ED (2012) The KMN protein network–chief conductors of the kinetochore orchestra. J Cell Sci 125:5927–5936. doi:10.1242/jcs.093724
Vink M, Simonetta M, Transidico P et al (2006) In vitro FRAP identifies the minimal requirements for Mad2 kinetochore dynamics. Curr Biol 16:755–766. doi:10.1016/j.cub.2006.03.057
Vleugel M, Hoogendoorn E, Snel B, Kops GJPL (2012) Evolution and function of the mitotic checkpoint. Dev Cell 23:239–250. doi:10.1016/j.devcel.2012.06.013
Vleugel M, Tromer E, Omerzu M et al (2013) Arrayed BUB recruitment modules in the kinetochore scaffold KNL1 promote accurate chromosome segregation. J Cell Biol 203:943–955. doi:10.1083/jcb.201307016
Vleugel M, Hoek TA, Tromer E et al (2015a) Dissecting the roles of human BUB1 in the spindle assembly checkpoint. J Cell Sci 128:2975–2982. doi:10.1242/jcs.169821
Vleugel M, Omerzu M, Groenewold V et al (2015b) Sequential multisite phospho-regulation of KNL1-BUB3 interfaces at mitotic kinetochores. Mol Cell 57:824–835. doi:10.1016/j.molcel.2014.12.036
Vodermaier HC, Gieffers C, Maurer-Stroh S et al (2003) TPR subunits of the anaphase-promoting complex mediate binding to the activator protein CDH1. Curr Biol 13:1459–1468
Wang X, Babu JR, Harden JM et al (2001) The mitotic checkpoint protein hBUB3 and the mRNA export factor hRAE1 interact with GLE2p-binding sequence (GLEBS)-containing proteins. J Biol Chem 276:26559–26567. doi:10.1074/jbc.M101083200
Wang H, Hu X, Ding X et al (2004) Human Zwint-1 specifies localization of Zeste White 10 to kinetochores and is essential for mitotic checkpoint signaling. J Biol Chem 279:54590–54598. doi:10.1074/jbc.M407588200
Wang K, Sturt-Gillespie B, Hittle JC et al (2014) Thyroid hormone receptor interacting protein 13 (TRIP13) AAA-ATPase is a novel mitotic checkpoint-silencing protein. J Biol Chem 289:23928–23937. doi:10.1074/jbc.M114.585315
Wei RR, Al-Bassam J, Harrison SC (2007) The Ndc80/HEC1 complex is a contact point for kinetochore-microtubule attachment. Nat Struct Mol Biol 14:54–59. doi:10.1038/nsmb1186
Westhorpe FG, Tighe A, Lara-Gonzalez P, Taylor SS (2011) p31comet-mediated extraction of Mad2 from the MCC promotes efficient mitotic exit. J Cell Sci 124:3905–3916. doi:10.1242/jcs.093286
Wojtasz L, Daniel K, Roig I et al (2009) Mouse HORMAD1 and HORMAD2, two conserved meiotic chromosomal proteins, are depleted from synapsed chromosome axes with the help of TRIP13 AAA-ATPase. PLoS Genet 5:e1000702. doi:10.1371/journal.pgen.1000702
Xia G, Luo X, Habu T et al (2004) Conformation-specific binding of p31(comet) antagonizes the function of Mad2 in the spindle checkpoint. EMBO J 23:3133–3143. doi:10.1038/sj.emboj.7600322
Yamagishi Y, Yang C-H, Tanno Y, Watanabe Y (2012) MPS1/Mph1 phosphorylates the kinetochore protein KNL1/Spc7 to recruit SAC components. Nat Cell Biol 14:746–752. doi:10.1038/ncb2515
Yamaguchi M, VanderLinden R, Weissmann F et al (2016) Cryo-EM of mitotic checkpoint complex-bound APC/C reveals reciprocal and conformational regulation of ubiquitin ligation. Mol Cell 63:593–607. doi:10.1016/j.molcel.2016.07.003
Yamamoto TG, Watanabe S, Essex A, Kitagawa R (2008) SPDL-1 functions as a kinetochore receptor for MDF-1 in Caenorhabditis elegans. J Cell Biol 183:187–194. doi:10.1083/jcb.200805185
Yang M, Li B, Tomchick DR et al (2007) p31comet blocks Mad2 activation through structural mimicry. Cell 131:744–755. doi:10.1016/j.cell.2007.08.048
Ye Q, Rosenberg SC, Moeller A et al (2015) TRIP13 is a protein-remodeling AAA + ATPase that catalyzes MAD2 conformation switching. Elife 4:213. doi:10.7554/eLife.07367
Zachariae W, Schwab M, Nasmyth K, Seufert W (1998) Control of cyclin ubiquitination by CDK-regulated binding of Hct1 to the anaphase promoting complex. Science 282:1721–1724
Zhang Y, Lees E (2001) Identification of an overlapping binding domain on Cdc20 for Mad2 and anaphase-promoting complex: model for spindle checkpoint regulation. Mol Cell Biol 21:5190–5199. doi:10.1128/MCB.21.15.5190-5199.2001
Zhang G, Lischetti T, Nilsson J (2014) A minimal number of MELT repeats supports all the functions of KNL1 in chromosome segregation. J Cell Sci 127:871–884. doi:10.1242/jcs.139725
Zhang G, Lischetti T, Hayward DG, Nilsson J (2015) Distinct domains in Bub1 localize RZZ and BubR1 to kinetochores to regulate the checkpoint. Nat Commun 6:7162. doi:10.1038/ncomms8162
Zhang G, Mendez BL, Sedgwick GG, Nilsson J (2016a) Two functionally distinct kinetochore pools of BubR1 ensure accurate chromosome segregation. Nat Commun 7:12256. doi:10.1038/ncomms12256
Zhang H, Liu S-T, Department of Biological Sciences, University of Toledo, 2801 West Bancroft St., Toledo, OH 43606, USA (2016b) The mitotic checkpoint complex (MCC): looking back and forth after 15 years. AIMS Mol Sci 3:597–634. doi:10.3934/molsci.2016.4.597
Zhang S, Chang L, Alfieri C et al (2016c) Molecular mechanism of APC/C activation by mitotic phosphorylation. Nature 533:260–264. doi:10.1038/nature17973
Zhu T, Dou Z, Qin B et al (2013) Phosphorylation of microtubule-binding protein Hec1 by mitotic kinase Aurora B specifies spindle checkpoint kinase Mps1 signaling at the kinetochore. J Biol Chem 288:36149–36159. doi:10.1074/jbc.M113.507970
Acknowledgements
Thanks to Dhanya Cheerambathur, Pablo Lara-Gonzalez, and Arshad Desai for critical reading and input on the manuscript, and Andrea Musacchio and Scott Schuyler for sharing unpublished results. K.D.C. gratefully acknowledges support from the March of Dimes Foundation, National Institutes of Health (R01 GM104141), and the Ludwig Institute for Cancer Research.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2017 Springer International Publishing AG
About this chapter
Cite this chapter
Corbett, K.D. (2017). Molecular Mechanisms of Spindle Assembly Checkpoint Activation and Silencing. In: Black, B. (eds) Centromeres and Kinetochores. Progress in Molecular and Subcellular Biology, vol 56. Springer, Cham. https://doi.org/10.1007/978-3-319-58592-5_18
Download citation
DOI: https://doi.org/10.1007/978-3-319-58592-5_18
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-58591-8
Online ISBN: 978-3-319-58592-5
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)