The Role of the Kinetochore in Spindle Checkpoint Signaling

  • P. Todd Stukenberg
  • Daniel J. Burke


It was observed, with the advent of live cell imaging in the 1950s, that cells did not enter into anaphase until the last chromosomes arrived at the metaphase plate suggesting intricate regulation between chromosome movements and cell cycle progression (Carlson, 1956; Bajer and Mole-Bajer, 1961). Spermatocytes of praying mantids provided a dramatic demonstration of this intricate regulation (Callan and Jacobs, 1957). Male mantids have X1X2Y sex determination, a result of an ancient event that split the X chromosome in two. During meiosis the X1X2Y trivalent must disjoin to produce an X1X2–containing gamete and a Y-containing gamete. However, there is chromosome misalignment in 10% of meiotic divisions producing an X-Y bivalent and one X chromosome that is unaligned at metaphase. Interestingly, cells with the unaligned X chromosome remain arrested at metaphase of meiosis I. Callan and Jacobs (1957) proposed that cells sense the single unaligned chromosome and inhibit the...


Kinetochore Protein Spindle Checkpoint Checkpoint Protein Microtubule Binding Sister Kinetochore 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



We thank Sue Biggins and the members of the Stukenberg and Burke labs for helpful discussions and comments on the manuscript. We also thank Mitsuhiro Yanagida, Mark Jackman, and Jonathon Pines for communicating results prior to publication. We apologize to those colleagues whose work was not cited due to space limitations.


  1. Abrieu, A., Magnaghi-Jaulin, L., Kahana, J.A., Peter, M., Castro, A., Vigneron, S., Lorca, T., Cleveland, D.W., and Labbe, J.C. (2001). Mps1 is a kinetochore-associated kinase essential for the vertebrate mitotic checkpoint. Cell 106, 83–93.PubMedGoogle Scholar
  2. Ahonen, L.J., Kallio, M.J., Daum, J.R., Bolton, M., Manke, I.A., Yaffe, M.B., Stukenberg, P.T., and Gorbsky, G.J. (2005). Polo-like kinase 1 creates the tension-sensing 3F3/2 phosphoepitope and modulates the association of spindle-checkpoint proteins at kinetochores. Curr Biol 15, 1078–89.PubMedGoogle Scholar
  3. Ault, J.G. and Nicklas, R.B. (1989). Tension, microtubule rearrangements, and the proper distribution of chromosomes in mitosis. Chromosoma 98, 33–9.PubMedGoogle Scholar
  4. Bajer, A. and Mole-Bajer, J. (1961). UV microbeam irradiation of chromosomes during mitosis in endosperm. Exp Cell Res 25, 251–267.PubMedGoogle Scholar
  5. Basto, R., Gomes, R., and Karess, R.E. (2000). Rough deal and Zw10 are required for the metaphase checkpoint in Drosophila. Nat Cell Biol 2, 939–43.PubMedGoogle Scholar
  6. Basto, R., Scaerou, F., Mische, S., Wojcik, E., Lefebvre, C., Gomes, R., Hays, T., and Karess, R. (2004). In vivo dynamics of the rough deal checkpoint protein during Drosophila mitosis. Curr Biol 14, 56–61.PubMedGoogle Scholar
  7. Baumann, C., Korner, R., Hofmann, K., and Nigg, E.A. (2007). PICH, a centromere-associated SNF2 family ATPase, is regulated by Plk1 and required for the spindle checkpoint. Cell 128, 101–114.PubMedGoogle Scholar
  8. Biggins, S. and Murray, A.W. (2001). The budding yeast protein kinase Ipl1/Aurora allows the absence of tension to activate the spindle checkpoint. Genes Dev 15, 3118–3129.PubMedGoogle Scholar
  9. Boyarchuk, Y., Salic, A., Dasso, M., and Arnaoutov, A. (2007). Bub1 is essential for assembly of the functional inner centromere. J Cell Biol 176, 919–28.PubMedGoogle Scholar
  10. Brown, M.T., Goetsch, L., and Hartwell, L.H. (1993). MIF2 is required for mitotic spindle integrity during anaphase spindle elongation in Saccharomyces cerevisiae. J Cell Biol 123(2), 387–403.PubMedGoogle Scholar
  11. Buffin, E., Emre, D., and Karess, R.E. (2007). Flies without a spindle checkpoint. Nat Cell Biol 9, 565–72.PubMedGoogle Scholar
  12. Callan, H. G and Jacobs, P. A. (1957). The meiotic process in Mantis Religiosa L. males. J.Genetics 200, 200–217.Google Scholar
  13. Carlson, J.G. (1956). On the mitotic movements of chromosomes. Science 124, 203–206.PubMedGoogle Scholar
  14. Carvalho, A., Carmena, M., Sambade, C., Earnshaw, W.C., and Wheatley, S.P. (2003). Survivin is required for stable checkpoint activation in taxol-treated HeLa cells. J Cell Sci 116, 2987–2998.PubMedGoogle Scholar
  15. Chan, G.K., Jablonski, S.A., Starr, D.A., Goldberg, M.L., and Yen, T.J. (2000). Human Zw10 and ROD are mitotic checkpoint proteins that bind to kinetochores. Nat Cell Biol 2, 944–7.PubMedGoogle Scholar
  16. Chan, G.K., Jablonski, S.A., Sudakin, V., Hittle, J.C., and Yen, T.J. (1999). Human BUBR1 is a mitotic checkpoint kinase that monitors CENP-E functions at kinetochores and binds the cyclosome/APC. J Cell Biol 146, 941–54.PubMedGoogle Scholar
  17. Chan, G.K., Schaar, B.T., and Yen, T.J. (1998). Characterization of the kinetochore binding domain of CENP-E reveals interactions with the kinetochore proteins CENP-F and hBUBR1. J Cell Biol 143, 49–63.PubMedGoogle Scholar
  18. Cheeseman, I.M., Chappie, J.S., Wilson-Kubalek, E.M., and Desai, A. (2006). The conserved KMN network constitutes the core microtubule-binding site of the kinetochore. Cell 127, 983–97.PubMedGoogle Scholar
  19. Cheeseman, I.M., Drubin, D.G., and Barnes, G. (2002). Simple centromere, complex kinetochore: linking spindle microtubules and centromeric DNA in budding yeast. J Cell Biol 157, 199–203.PubMedGoogle Scholar
  20. Cheeseman, I.M., Enquist-Newman, M., Muller-Reichert, T., Drubin, D.G., and Barnes, G. (2001). Mitotic spindle integrity and kinetochore function linked by the Duo1p/Dam1p complex. J Cell Biol 152, 197–212.PubMedGoogle Scholar
  21. Cheeseman, I.M., Niessen, S., Anderson, S., Hyndman, F., Yates, J.R.3., Oegema, K., and Desai, A. (2004). A conserved protein network controls assembly of the outer kinetochore and its ability to sustain tension. Genes Dev 18, 2255–68.PubMedGoogle Scholar
  22. Chen, R.H. (2002). BubR1 is essential for kinetochore localization of other spindle checkpoint proteins and its phosphorylation requires Mad1. J Cell Biol 158, 487–96.PubMedGoogle Scholar
  23. Chen, R.H. (2004). Phosphorylation and activation of Bub1 on unattached chromosomes facilitate the spindle checkpoint. EMBO J 23, 3113–3121.PubMedGoogle Scholar
  24. Chen, R.H., Shevchenko, A., Mann, M., and Murray, A.W. (1998). Spindle checkpoint protein Xmad1 recruits Xmad2 to unattached kinetochores. J Cell Biol 143, 283–95.PubMedGoogle Scholar
  25. Chen, R.H., Waters, J.C., Salmon, E.D., and Murray, A.W. (1996). Association of spindle assembly checkpoint component XMAD2 with unattached kinetochores. Science 274, 242–6.PubMedGoogle Scholar
  26. Chung, E. and Chen, R.H. (2003). Phosphorylation of Cdc20 is required for its inhibition by the spindle checkpoint. Nat Cell Biol 5, 748–753.PubMedGoogle Scholar
  27. Cleveland, D.W., Mao, Y., and Sullivan, K.F. (2003). Centromeres and kinetochores: from epigenetics to mitotic checkpoint signaling. Cell 112, 407–421.PubMedGoogle Scholar
  28. De Wulf, P., McAinsh, A.D., and Sorger, P.K. (2003). Hierarchical assembly of the budding yeast kinetochore from multiple subcomplexes. Genes Dev 17, 2902–2921.PubMedGoogle Scholar
  29. DeLuca, J.G., Dong, Y., Hergert, P., Strauss, J., Hickey, J.M., Salmon, E.D., and McEwen, B.F. (2005). Hec1 and nuf2 are core components of the kinetochore outer plate essential for organizing microtubule attachment sites. Mol Biol Cell 16, 519–31.PubMedGoogle Scholar
  30. DeLuca, J.G., Moree, B., Hickey, J.M., Kilmartin, J.V., and Salmon, E.D. (2002). hNuf2 inhibition blocks stable kinetochore-microtubule attachment and induces mitotic cell death in HeLa cells. J Cell Biol 159, 549–55.PubMedGoogle Scholar
  31. Dewar, H., Tanaka, K., Nasmyth, K., and Tanaka, T.U. (2004). Tension between two kinetochores suffices for their bi-orientation on the mitotic spindle. Nature 428, 93–97.PubMedGoogle Scholar
  32. Ditchfield, C., Johnson, V.L., Tighe, A., Ellston, R., Haworth, C., Johnson, T., Mortlock, A., Keen, N., and Taylor, S.S. (2003). Aurora B couples chromosome alignment with anaphase by targeting BubR1, Mad2, and Cenp-E to kinetochores. J Cell Biol 161, 267–80.PubMedGoogle Scholar
  33. Dohmen, R.J. and Varshavsky, A. (2005). Heat-inducible degron and the making of conditional mutants. Methods Enzymol. 399, 799–822.Google Scholar
  34. Draviam, V.M., Stegmeier, F., Nalepa, G., Sowa, M.E., Chen, J., Liang, A., Hannon, G.J., Sorger, P.K., Harper, J.W., and Elledge, S.J. (2007). A functional genomic screen identifies a role for TAO1 kinase in spindle-checkpoint signalling. Nat Cell Biol 9, 556–64.PubMedGoogle Scholar
  35. Elion, E.A. (2001). The Ste5p scaffold. J. Cell Sci. 114, 3967–3978.PubMedGoogle Scholar
  36. Emanuele, M., Burke, D.J., and Stukenberg, P.T. (2007). A Hec of a microtubule attachment. Nat Struct Mol Biol 14, 11–3.PubMedGoogle Scholar
  37. Emanuele, M.J., McCleland, M.L., Satinover, D.L., and Stukenberg, P.T. (2005). Measuring the Stoichiometry and Physical Interactions between Components Elucidates the Architecture of the Vertebrate Kinetochore. Mol Biol Cell 16, 4882–4892.PubMedGoogle Scholar
  38. Fang, G. (2002). Checkpoint protein BubR1 acts synergistically with Mad2 to inhibit anaphase-promoting complex. Mol Biol Cell 13, 755–66.PubMedGoogle Scholar
  39. Fang, G., Yu, H., and Kirschner, M.W. (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, 1871–83.PubMedGoogle Scholar
  40. Fraschini, R., Beretta, A., Sironi, L., Musacchio, A., Lucchini, G., and Piatti, S. (2001). Bub3 interaction with Mad2, Mad3 and Cdc20 is mediated by WD40 repeats and does not require intact kinetochores. EMBO J. 20, 6648–6659.PubMedGoogle Scholar
  41. Gardner, R.D., Poddar, A., Yellman, C., Tavormina, P.A., Monteagudo, M.C., and Burke, D.J. (2001). The spindle checkpoint of the yeast Saccharomyces cerevisiae requires kinetochore function and maps to the CBF3 domain. Genetics 157, 1493–1502.PubMedGoogle Scholar
  42. Gillett, E.S., Espelin, C.W., and Sorger, P.K. (2004). Spindle checkpoint proteins and chromosome-microtubule attachment in budding yeast. J Cell Biol 164, 535–546.PubMedGoogle Scholar
  43. Goh, P.Y. and Kilmartin, J.V. (1993). NDC10: a gene involved in chromosome segregation in Saccharomyces cerevisiae. J Cell Biol 121, 503–12.PubMedGoogle Scholar
  44. Goshima, G., Kiyomitsu, T., Yoda, K., and Yanagida, M. (2003). Human centromere chromatin protein hMis12, essential for equal segregation, is independent of CENP-A loading pathway. J Cell Biol 160, 25–39.PubMedGoogle Scholar
  45. Hardwick, K.G., Johnston, R.C., Smith, D.L., and Murray, A.W. (2000). MAD3 encodes a novel component of the spindle checkpoint which interacts with Bub3p, Cdc20p, and Mad2p. J. Cell Biol. 148, 871–882.PubMedGoogle Scholar
  46. Hartwell, L.H. (1978). Cell division from a genetic perspective. J Cell Biol 77, 627–637.PubMedGoogle Scholar
  47. Hartwell, L.H. and Weinert, T.A. (1989). Checkpoints: controls that ensure the order of cell cycle events. Science 246, 629–634.PubMedGoogle Scholar
  48. Hauf, S., Cole, R.W., LaTerra, S., Zimmer, C., Schnapp, G., Walter, R., Heckel, A., van Meel, J., Rieder, C.L., and Peters, J.M. (2003). The small molecule Hesperadin reveals a role for Aurora B in correcting kinetochore-microtubule attachment and in maintaining the spindle assembly checkpoint. J Cell Biol 161, 281–94.PubMedGoogle Scholar
  49. He, X., Rines, D.R., Espelin, C.W., and Sorger, P.K. (2001). Molecular analysis of kinetochore-microtubule attachment in budding yeast. Cell 106, 195–206.PubMedGoogle Scholar
  50. Howell, B.J., McEwen, B.F., Canman, J.C., Hoffman, D.B., Farrar, E.M., Rieder, C.L., and Salmon, E.D. (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, 1159–72.PubMedGoogle Scholar
  51. Howell, B.J., Moree, B., Farrar, E.M., Stewart, S., Fang, G., and Salmon, E.D. (2004). Spindle checkpoint protein dynamics at kinetochores in living cells. Curr Biol 14, 953–964.PubMedGoogle Scholar
  52. Hoyt, M.A., Totis, L., and Roberts, B.T. (1991). S. cerevisiae genes required for cell cycle arrest in response to loss of microtubule function. Cell 66, 507–517.PubMedGoogle Scholar
  53. Hwang, L.H., Lau, L.F., Smith, D.L., Mistrot, C.A., Hardwick, K.G., Hwang, E.S., Amon, A., and Murray, A.W. (1998). Budding yeast Cdc20: a target of the spindle checkpoint. Science 279, 1041–1044.PubMedGoogle Scholar
  54. Indjeian, V.B., Stern, B.M., and Murray, A.W. (2005). The centromeric protein Sgo1 is required to sense lack of tension on mitotic chromosomes. Science 307, 130–133.PubMedGoogle Scholar
  55. Jacobs, C.W., Adams, A.E., Szaniszlo, P.J., and Pringle, J.R. (1988). Functions of microtubules in the Saccharomyces cerevisiae cell cycle. J Cell Biol 107, 1409–1426.PubMedGoogle Scholar
  56. Janke, C., Ortiz, J., Lechner, J., Shevchenko, A., Shevchenko, A., Magiera, M.M., Schramm, C., and Schiebel, E. (2001). The budding yeast proteins Spc24p and Spc25p interact with Ndc80p and Nuf2p at the kinetochore and are important for kinetochore clustering and checkpoint control. EMBO J 20, 777–791.PubMedGoogle Scholar
  57. Jones, M.H., Huneycutt, B.J., Pearson, C.G., Zhang, C., Morgan, G., Shokat, K., Bloom, K., and Winey, M. (2005). Chemical genetics reveals a role for Mps1 kinase in kinetochore attachment during mitosis. Curr Biol 15, 160–165.PubMedGoogle Scholar
  58. Kallio, M.J., Beardmore, V.A., Weinstein, J., and Gorbsky, G.J. (2002a). Rapid microtubule-independent dynamics of Cdc20 at kinetochores and centrosomes in mammalian cells. J Cell Biol 158, 841–847.Google Scholar
  59. Kallio, M.J., McCleland, M.L., Stukenberg, P.T., and Gorbsky, G.J. (2002b). Inhibition of aurora B kinase blocks chromosome segregation, overrides the spindle checkpoint, and perturbs microtubule dynamics in mitosis. Curr Biol 12, 900–5.Google Scholar
  60. King, E.M., Rachidi, N., Morrice, N., Hardwick, K.G., and Stark, M.J. (2007). Ipl1p-dependent phosphorylation of Mad3p is required for the spindle checkpoint response to lack of tension at kinetochores. Genes Dev 21(10), 1163–8.Google Scholar
  61. Kitagawa, K., Abdulle, R., Bansal, P.K., Cagney, G., Fields, S., and Hieter, P. (2003). Requirement of Skp1-Bub1 interaction for kinetochore-mediated activation of the spindle checkpoint. Mol Cell 11, 1201–1213.PubMedGoogle Scholar
  62. Kitajima, T.S., Hauf, S., Ohsugi, M., Yamamoto, T., and Watanabe, Y. (2005). Human Bub1 defines the persistent cohesion site along the mitotic chromosome by affecting Shugoshin localization. Curr Biol 15, 353–9.PubMedGoogle Scholar
  63. Kitajima, T.S., Kawashima, S.A., and Watanabe, Y. (2004). The conserved kinetochore protein shugoshin protects centromeric cohesion during meiosis. Nature 427, 510–7.PubMedGoogle Scholar
  64. Kiyomitsu, T., Obuse, C., and Yanagida, M. (2007). Human Blinkin/AF15q14 is required for chromosome alignment and the mitotic checkpoint through direct interaction with Bub1 and BubR1. Dev Cell 13(5), 663–76.PubMedGoogle Scholar
  65. Kops, G.J., Kim, Y., Weaver, B.A., Mao, Y., McLeod, I., Yates, J.R.3., Tagaya, M., and Cleveland, D.W. (2005). ZW10 links mitotic checkpoint signaling to the structural kinetochore. J Cell Biol 169, 49–60.Google Scholar
  66. Kosco, K.A., Pearson, C.G., Maddox, P.S., Wang, P.J., Adams, I.R., Salmon, E.D., Bloom, K., and Huffaker, T.C. (2001). Control of microtubule dynamics by Stu2p is essential for spindle orientation and metaphase chromosome alignment in yeast. Mol Biol Cell 12, 2870–2880.PubMedGoogle Scholar
  67. Lew, D.J. and Burke, D.J. (2003). The spindle assembly and spindle position checkpoints. Annu Rev Genet 37, 251–282.PubMedGoogle Scholar
  68. Li, R. and Murray, A.W. (1991). Feedback control of mitosis in budding yeast. Cell 66, 519–531.PubMedGoogle Scholar
  69. Li, X. and Nicklas, R.B. (1995). Mitotic forces control a cell-cycle checkpoint. Nature 373, 630–632.PubMedGoogle Scholar
  70. Li, Y. and Benezra, R. (1996). Identification of a human mitotic checkpoint gene: hsMAD2. Science 274, 246–8.PubMedGoogle Scholar
  71. Liu, S.T., Chan, G.K., Hittle, J.C., Fujii, G., Lees, E., and Yen, T.J. (2003). Human MPS1 kinase is required for mitotic arrest induced by the loss of CENP-E from kinetochores. Mol Biol Cell 14, 1638–51.PubMedGoogle Scholar
  72. Lou, Y., Yao, J., Zereshki, A., Dou, Z., Ahmed, K., Wang, H., Hu, J., Wang, Y., and Yao, X. (2004). NEK2A interacts with MAD1 and possibly functions as a novel integrator of the spindle checkpoint signaling. J Biol Chem 279, 20049–57.PubMedGoogle Scholar
  73. Lucchini, G., Falconi, M.M., Pizzagalli, A., Aguilera, A., Klein, H.L., and Plevani, P. (1990). Nucleotide sequence and characterization of temperature-sensitive pol1 mutants of Saccharomyces cerevisiae. Gene 90, 99–104.PubMedGoogle Scholar
  74. Luo, X., Fang, G., Coldiron, M., Lin, Y., Yu, H., Kirschner, M.W., and Wagner, G. (2000). Structure of the Mad2 spindle assembly checkpoint protein and its interaction with Cdc20. Nat Struct. Biol. 7, 224–229.Google Scholar
  75. Luo, X., Tang, Z., Rizo, J., and 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.PubMedGoogle Scholar
  76. Mao, Y., Abrieu, A., and Cleveland, D.W. (2003). Activating and silencing the mitotic checkpoint through CENP-E-dependent activation/inactivation of BubR1. Cell 114, 87–98.PubMedGoogle Scholar
  77. Mao, Y., Desai, A., and Cleveland, D.W. (2005). Microtubule capture by CENP-E silences BubR1-dependent mitotic checkpoint signaling. J Cell Biol 170, 873–80.PubMedGoogle Scholar
  78. Martin-Lluesma, S., Stucke, V.M., and Nigg, E.A. (2002). Role of Hec1 in spindle checkpoint signaling and kinetochore recruitment of Mad1/Mad2. Science 297, 2267–70.PubMedGoogle Scholar
  79. McAinsh, A.D., Meraldi, P., Draviam, V.M., Toso, A., and Sorger, P.K. (2006). The human kinetochore proteins Nnf1R and Mcm21R are required for accurate chromosome segregation. Embo J 25, 4033–49.PubMedGoogle Scholar
  80. McAinsh, A.D., Tytell, J.D., and Sorger, P.K. (2003). Structure, function, and regulation of budding yeast kinetochores. Annu Rev Cell Dev Biol 19, 519–539.PubMedGoogle Scholar
  81. McCarroll, R.M. and Fangman, W.L. (1988). Time of replication of yeast centromeres and telomeres. Cell 54, 505–513.PubMedGoogle Scholar
  82. McCleland, M.L., Gardner, R.D., Kallio, M.J., Daum, J.R., Gorbsky, G.J., Burke, D.J., and Stukenberg, P.T. (2003). The highly conserved Ndc80 complex is required for kinetochore assembly, chromosome congression, and spindle checkpoint activity. Genes Dev 17, 101–114.PubMedGoogle Scholar
  83. McCleland, M.L., Kallio, M.J., Barrett-Wilt, G.A., Kestner, C.A., Shabanowitz, J., Hunt, D.F., Gorbsky, G.J., and Stukenberg, P.T. (2004). The vertebrate Ndc80 complex contains Spc24 and Spc25 homologs, which are required to establish and maintain kinetochore-microtubule attachment. Curr Biol 14, 131–7.PubMedGoogle Scholar
  84. McIntosh, J.R. (1991). Structural and mechanical control of mitotic progression. Cold Spring Harb Symp Quant Biol 56, 613–619.PubMedGoogle Scholar
  85. Meraldi, P., Draviam, V.M., and Sorger, P.K. (2004). Timing and checkpoints in the regulation of mitotic progression. Dev Cell 7, 45–60.PubMedGoogle Scholar
  86. Meraldi, P. and Sorger, P.K. (2005). A dual role for Bub1 in the spindle checkpoint and chromosome congression. Embo J 24, 1621–33.PubMedGoogle Scholar
  87. Minshull, J., Sun, H., Tonks, N.K., and Murray, A.W. (1994). A MAP kinase-dependent spindle assembly checkpoint in Xenopus egg extracts. Cell 79, 475–86.PubMedGoogle Scholar
  88. Mizuguchi, G., Xiao, H., Wisniewski, J., Smith, M.M., and Wu, C. (2007). Nonhistone Scm3 and histones CenH3-H4 assemble the core of centromere-specific nucleosomes. Cell 129(6), 1153–64.PubMedGoogle Scholar
  89. Murray, D., Mirzayans, R., and Chen, R.H. (1999). Spindle checkpoint protein Xmad1 recruits Xmad2 to unattached kinetochores. Br J Cancer 81, 959–65.PubMedGoogle Scholar
  90. Musacchio, A. and Hardwick, K.G. (2002). The spindle checkpoint: structural insights into dynamic signalling. Nat Rev Mol Cell Biol 3, 731–741.PubMedGoogle Scholar
  91. Musacchio, A. and Salmon, E.D. (2007). The spindle-assembly checkpoint in space and time. Nat Rev Mol Cell Biol 8, 379–393.PubMedGoogle Scholar
  92. Nasmyth, K. (2002). Segregating sister genomes: the molecular biology of chromosome separation. Science 297, 559–565.PubMedGoogle Scholar
  93. Nekrasov, V.S., Smith, M.A., Peak-Chew, S., and Kilmartin, J.V. (2003). Interactions between centromere complexes in Saccharomyces cerevisiae. Mol Biol Cell 14, 4931–4946.PubMedGoogle Scholar
  94. Nicklas, R.B., Ward, S.C., and Gorbsky, G.J. (1995). Kinetochore chemistry is sensitive to tension and may link mitotic forces to a cell cycle checkpoint. J Cell Biol 130, 929–939.Google Scholar
  95. Pinsky, B.A., Kung, C., Shokat, K.M., and Biggins, S. (2006). The Ipl1-Aurora protein kinase activates the spindle checkpoint by creating unattached kinetochores. Nat Cell Biol 8, 78–83.PubMedGoogle Scholar
  96. Poddar, A., Stukenberg, P.T., and Burke, D.J. (2005). Two complexes of spindle checkpoint proteins containing Cdc20 and Mad2 assemble during mitosis independently of the kinetochore in Saccharomyces cerevisiae. Eukaryot Cell 4, 867–878.PubMedGoogle Scholar
  97. Putkey, F.R., Cramer, T., Morphew, M.K., Silk, A.D., Johnson, R.S., McIntosh, J.R., and Cleveland, D.W. (2002). Unstable kinetochore-microtubule capture and chromosomal instability following deletion of CENP-E. Dev Cell 3, 351–65.PubMedGoogle Scholar
  98. Qi, W., Tang, Z., and Yu, H. (2006). Phosphorylation- and polo-box-dependent binding of Plk1 to Bub1 is required for the kinetochore localization of Plk1. Mol Biol Cell 17, 3705–16.PubMedGoogle Scholar
  99. Rieder, C.L., Cole, R.W., Khodjakov, A., and 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.PubMedGoogle Scholar
  100. Robbins, A.R., Jablonski, S.A., Yen, T.J., Yoda, K., Robey, R., Bates, S.E., and Sackett, D.L. (2005). Inhibitors of histone deacetylases alter kinetochore assembly by disrupting pericentromeric heterochromatin. Cell Cycle 4, 717–26.PubMedGoogle Scholar
  101. Rosasco-Nitcher, S.E., Lan, W., Khorasanizadeh, S., Stukenberg, P.T. (2008) Centromeric Aurora-B activation requires TD-60, microtubules, and substrate priming phosphorylation. Science 319(5862), 469–7PubMedGoogle Scholar
  102. Sharp-Baker, H. and Chen, R.H. (2001). Spindle checkpoint protein Bub1 is required for kinetochore localization of Mad1, Mad2, Bub3, and CENP-E, independently of its kinase activity. J Cell Biol 153, 1239–50.PubMedGoogle Scholar
  103. Siller, K.H., Serr, M., Steward, R., Hays, T.S., and Doe, C.Q. (2005). Live imaging of Drosophila brain neuroblasts reveals a role for Lis1/dynactin in spindle assembly and mitotic checkpoint control. Mol Biol Cell 16, 5127–40.PubMedGoogle Scholar
  104. Sironi, L., Mapelli, M., Knapp, S., De Antoni, A., Jeang, K.T., and Musacchio, A. (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.PubMedGoogle Scholar
  105. Skoufias, D.A., Andreassen, P.R., Lacroix, F.B., Wilson, L., and Margolis, R.L. (2001). Mammalian mad2 and bub1/bubR1 recognize distinct spindle-attachment and kinetochore-tension checkpoints. Proc Natl Acad Sci USA 98, 4492–7.Google Scholar
  106. Starr, D.A., Williams, B.C., Hays, T.S., and Goldberg, M.L. (1998). ZW10 helps recruit dynactin and dynein to the kinetochore. J Cell Biol 142, 763–74.PubMedGoogle Scholar
  107. Stern, B.M. and Murray, A.W. (2001). Lack of tension at kinetochores activates the spindle checkpoint in budding yeast. Curr Biol 11, 1462–1467.PubMedGoogle Scholar
  108. Stoler, S., Keith, K.C., Curnick, K.E., and Fitzgerald-Hayes, M. (1995). A mutation in CSE4, an essential gene encoding a novel chromatin-associated protein in yeast, causes chromosome nondisjunction and cell cycle arrest at mitosis. Genes Dev 9(5), 573–86.PubMedGoogle Scholar
  109. Stoler, S., Rogers, K., Weitze, S., Morey, L., Fitzgerald-Hayes, M., Baker, R.E. (2007). Scm3, an essential Saccharomyces cerevisiae centromere protein required for G2/M progression and Cse4 localization. Proc Natl Acad Sci U S A 104(25), 10571–6 (Epub 2007 Jun 4).PubMedGoogle Scholar
  110. Stucke, V.M., Baumann, C., and Nigg, E.A. (2004). Kinetochore localization and microtubule interaction of the human spindle checkpoint kinase Mps1. Chromosoma 113, 1–15.PubMedGoogle Scholar
  111. Stucke, V.M., Sillje, H.H., Arnaud, L., and Nigg, E.A. (2002). Human Mps1 kinase is required for the spindle assembly checkpoint but not for centrosome duplication. Embo J 21, 1723–32.PubMedGoogle Scholar
  112. Sudakin, V. and Yen, T.J. (2004). Purification of the mitotic checkpoint complex, an inhibitor of the APC/C from HeLa cells. Methods Mol Biol 281, 199–212.PubMedGoogle Scholar
  113. Tanaka, T.U., Rachidi, N., Janke, C., Pereira, G., Galova, M., Schiebel, E., Stark, M.J., and Nasmyth, K. (2002). Evidence that the Ipl1-Sli15 (Aurora kinase-INCENP) complex promotes chromosome bi-orientation by altering kinetochore-spindle pole connections. Cell 108, 317–329.PubMedGoogle Scholar
  114. Tang, Z., Shu, H., Oncel, D., Chen, S., and Yu, H. (2004). Phosphorylation of Cdc20 by Bub1 provides a catalytic mechanism for APC/C inhibition by the spindle checkpoint. Mol. Cell 16, 387–397.PubMedGoogle Scholar
  115. Tavormina, P.A. and Burke, D.J. (1998). Cell cycle arrest in cdc20 mutants of Saccharomyces cerevisiae is independent of Ndc10p and kinetochore function but requires a subset of spindle checkpoint genes. Genetics 148, 1701–1713.PubMedGoogle Scholar
  116. Taylor, S.S., Ha, E., and 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.PubMedGoogle Scholar
  117. Taylor, S.S. and McKeon, F. (1997). Kinetochore localization of murine Bub1 is required for normal mitotic timing and checkpoint response to spindle damage. Cell 89, 727–35.PubMedGoogle Scholar
  118. Vader, G., Cruijsen, C.W., van Harn, T., Vromans, M.J., Medema, R.H., Lens, S.M. (2007). The chromosomal passenger complex controls spindle checkpoint function independent from its role in correcting microtubule kinetochore interactions. Mol Biol Cell 18(11), 4553–64 (Epub 2007 Aug 15).Google Scholar
  119. Vink, M., Simonetta, M., Transidico, P., Ferrari, K., Mapelli, M., De Antoni, A., Massimiliano, L., Ciliberto, A., Faretta, M., Salmon, E.D., and Musacchio, A. (2006). In vitro FRAP identifies the minimal requirements for Mad2 kinetochore dynamics. Curr Biol 16, 755–766.PubMedGoogle Scholar
  120. Wang, H., Hu, X., Ding, X., Dou, Z., Yang, Z., Shaw, A.W., Teng, M., Cleveland, D.W., Goldberg, M.L., Niu, L., and Yao, X. (2004). Human Zwint-1 specifies localization of Zeste White 10 to kinetochores and is essential for mitotic checkpoint signaling. J Biol Chem 279, 54590–8.PubMedGoogle Scholar
  121. Waters, J.C., Chen, R.H., Murray, A.W., Gorbsky, G.J., Salmon, E.D., and Nicklas, R.B. (1999). Mad2 binding by phosphorylated kinetochores links error detection and checkpoint action in mitosis. Curr Biol 9, 649–652.PubMedGoogle Scholar
  122. Waters, J.C., Chen, R.H., Murray, A.W., and Salmon, E.D. (1998). Localization of Mad2 to kinetochores depends on microtubule attachment, not tension. J Cell Biol 141, 1181–91.PubMedGoogle Scholar
  123. Weaver, B.A., Bonday, Z.Q., Putkey, F.R., Kops, G.J., Silk, A.D., and Cleveland, D.W. (2003). Centromere-associated protein-E is essential for the mammalian mitotic checkpoint to prevent aneuploidy due to single chromosome loss. J Cell Biol 162, 551–63.PubMedGoogle Scholar
  124. Wei, R.R., Al-Bassam, J., and Harrison, S.C. (2007). The Ndc80/HEC1 complex is a contact point for kinetochore-microtubule attachment. Nat Struct Mol Biol 14, 54–9.PubMedGoogle Scholar
  125. Weinert, T.A. and Hartwell, L.H. (1988). The RAD9 gene controls the cell cycle response to DNA damage in Saccharomyces cerevisiae. Science 241, 317–322.PubMedGoogle Scholar
  126. Weiss, E. and Winey, M. (1996). The Saccharomyces cerevisiae spindle pole body duplication gene MPS1 is part of a mitotic checkpoint. J Cell Biol 132, 111–123.PubMedGoogle Scholar
  127. Westermann, S., Cheeseman, I.M., Anderson, S., Yates, J.R., III, Drubin, D.G., and Barnes, G. (2003). Architecture of the budding yeast kinetochore reveals a conserved molecular core. J Cell Biol 163, 215–222.PubMedGoogle Scholar
  128. Wong, O.K. and Fang, G. (2005). Plx1 is the 3F3/2 kinase responsible for targeting spindle checkpoint proteins to kinetochores. J Cell Biol 170, 709–19.PubMedGoogle Scholar
  129. Yamamoto, A., Guacci, V., and Koshland, D. (1996). Pds1p, an inhibitor of anaphase in budding yeast, plays a critical role in the APC and checkpoint pathway(s). J Cell Biol 133, 99–110.PubMedGoogle Scholar
  130. Zecevic, M., Catling, A.D., Eblen, S.T., Renzi, L., Hittle, J.C., Yen, T.J., Gorbsky, G.J., and Weber, M.J. (1998). Active MAP kinase in mitosis: localization at kinetochores and association with the motor protein CENP-E. J Cell Biol 142, 1547–58.PubMedGoogle Scholar
  131. Zhao, Y. and Chen, R.H. (2006). Mps1 phosphorylation by MAP kinase is required for kinetochore localization of spindle-checkpoint proteins. Curr Biol 16, 1764–9.PubMedGoogle Scholar
  132. Zirkle, R.E. (1970). Ultraviolet-microbeam irradiation of newt-cell cytoplasm: spindle destruction, false anaphase, and delay of true anaphase. Radiat Res 41, 516–537.PubMedGoogle Scholar

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© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Department of Biochemistry and Molecular GeneticsUniversity of Virginia Medical CenterCharlottesvilleU.S.A

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