Molecular Mechanisms and Function of the Spindle Checkpoint, a Guardian of the Chromosome Stability

Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 676)


For equal segregation, chromosomes, which are distributed randomly in the nucleus of interphase, must be aligned at the spindle equator in mitosis before the onset of sister chromatid separation. The spindle checkpoint is a surveillance mechanism that delays the onset of sister chromatid separation while each chromosome is on the way to the spindle equator. Failure in the function of the checkpoint results in aneuploidy/polyploidy, which would be a cause of cancer. Here, we review chromosome dynamics in mitosis, molecular mechanisms of the spindle checkpoint and finally tumorigenesis triggered by missegregation of chromosomes.


Sister Chromatid Metaphase Plate Spindle Assembly Checkpoint Spindle Checkpoint Spindle Pole Body 
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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Funabiki H, Murray AW. The Xenopus chromokinesin Xkid is essential for metaphase chromosome alignment and must be degraded to allow anaphase chromosome movement. Cell 2000; 102:411–424.PubMedCrossRefGoogle Scholar
  2. 2.
    Levesque AA, Compton DA. The chromokinesin Kid is necessary for chromosome arm orientation and oscillation, but not congression, on mitotic spindles. J Cell Biol 2001; 154:1135–1146.PubMedCrossRefGoogle Scholar
  3. 3.
    Skibbens RV, Skeen VP, Salmon ED. Directional instability of kinetochore motility during chromosome congression and segregation in mitotic newt lung cells: a push-pull mechanism. J Cell Biol 1993; 122:859–875.PubMedCrossRefGoogle Scholar
  4. 4.
    Kapoor TM, Compton DA. Searching for the middle ground: mechanisms of chromosome alignment during mitosis. J Cell Biol 2002; 157:551–556.PubMedCrossRefGoogle Scholar
  5. 5.
    Kapoor TM, Lampson MA, Hergert P et al. Chromosomes can congress to the metaphase plate before biorientation. Science 2006; 311:388–391.PubMedCrossRefGoogle Scholar
  6. 6.
    Cleveland DW, Mao YH, Sullivan KF. Centromeres and kinetochores: From epigenetics to mitotic checkpoint signaling. Cell 2003; 112:407–421.PubMedCrossRefGoogle Scholar
  7. 7.
    Hwang LH, Lau LF, Smith DL et al. Budding yeast Cdc20: a target of the spindle checkpoint. Science 1998; 279:1041–1044.PubMedCrossRefGoogle Scholar
  8. 8.
    Kim SH, Lin DP, Matsumoto S et al. Fission yeast Slp1: An effector of the Mad2-dependent spindle checkpoint. Science 1998; 279:1045–1047.PubMedCrossRefGoogle Scholar
  9. 9.
    Peters JM. The anaphase promoting complex/cyclosome: a machine designed to destroy. Nat Rev Mol Cell Biol 2006; 7:644–656.PubMedCrossRefGoogle Scholar
  10. 10.
    Li R, Murray AW. Feedback control of mitosis in budding yeast. Cell 1991; 66:519–531.PubMedCrossRefGoogle Scholar
  11. 11.
    Hoyt MA, Totis L, Roberts BT. S. cerevisiae genes required for cell cycle arrest in response to loss of microtubule function. Cell 1991; 66:507–517.PubMedCrossRefGoogle Scholar
  12. 12.
    Winey M, Goetsch L, Baum P et al. MPS1 and MPS2: novel yeast genes defining distinct steps of spindle pole body duplication. J Cell Biol 1991; 114:745–754.PubMedCrossRefGoogle Scholar
  13. 13.
    Hardwick KG, Murray AW. Mad1p, a phosphoprotein component of the spindle assembly checkpoint in budding yeast. J Cell Biol 1995; 131:709–720.PubMedCrossRefGoogle Scholar
  14. 14.
    Karess R. Rod-Zw10-Zwilch: a key player in the spindle checkpoint. Trends Cell Biol 2005; 15:386–392.PubMedCrossRefGoogle Scholar
  15. 15.
    Habu T, Kim SH, Weinstein J et al. Identification of a MAD2-binding protein, CMT2 and its role in mitosis. EMBO J 2002; 21:6419–6228.PubMedCrossRefGoogle Scholar
  16. 16.
    Mao Y, Abrieu A, Cleveland DW. Activating and silencing the mitotic checkpoint through CENP-Edependent activation/inactivation of BubR1. Cell 2003; 114:87–98.PubMedCrossRefGoogle Scholar
  17. 17.
    Li X, Nicklas RB. Mitotic forces control a cell-cycle checkpoint. Nature 1995; 373:630–632.PubMedCrossRefGoogle Scholar
  18. 18.
    Rieder CL, Cole RW, Khodjakov A et al. The checkpoint delaying anaphase in response to chromosome monoorientation is mediated by an inhibitory signal produced by unattached kinetochores. J Cell Biol 1995; 130:941–948.PubMedCrossRefGoogle Scholar
  19. 19.
    Nicklas RB, Waters JC, Salmon ED et al. Checkpoint signals in grasshopper meiosis are sensitive to microtubule attachment, but tension is still essential. J Cell Sci 2001; 114:4173–4183.PubMedGoogle Scholar
  20. 20.
    Waters JC, Chen RH, Murray AW et al. Localization of Mad2 to kinetochores depends on microtubule attachment, not tension. J Cell Biol 1998; 141:1181–1191.PubMedCrossRefGoogle Scholar
  21. 21.
    Skoufias DA, Andreassen PR, Lacroix FB et al. Mammalian mad2 and bub1/bubR1 recognize distinct spindle-attachment and kinetochore-tension checkpoints. Proc Natl Acad Sci USA 2001; 98:4492–4497.PubMedCrossRefGoogle Scholar
  22. 22.
    Martin-Lluesma S, Stucke VM, Nigg EA. Role of Hec1 in spindle checkpoint signaling and kinetochore recruitment of Mad1/Mad2. Science 2002; 297:2267–2270.PubMedCrossRefGoogle Scholar
  23. 23.
    Hori T, Haraguchi T, Hiraoka Y et al. Dynamic behavior of Nuf2-Hec1 complex that localizes to the centrosome and centromere and is essential for mitotic progression in vertebrate cells. J Cell Sci 2003; 116:3347–3362.PubMedCrossRefGoogle Scholar
  24. 24.
    Sudakin V, Chan GK, Yen TJ. Checkpoint inhibition of the APC/C in HeLa cells is mediated by a complex of BUBR1, BUB3, CDC20 and MAD2. J Cell Biol 2001; 154:925–936.PubMedCrossRefGoogle Scholar
  25. 25.
    Luo X, Tang Z, Rizo J et al. The Mad2 spindle checkpoint protein undergoes similar major conformational changes upon binding to either Mad1 or Cdc20. Mol Cell 2002; 9:59–71.PubMedCrossRefGoogle Scholar
  26. 26.
    Sironi L, Mapelli M, Knapp S et al. Crystal structure of the tetrameric Mad1-Mad2 core complex: implications of a’ safety belt’ binding mechanism for the spindle checkpoint. EMBO J 2002; 21:2496–2506.PubMedCrossRefGoogle Scholar
  27. 27.
    Luo XL, Tang ZY, Xia GH et al. The Mad2 spindle checkpoint protein has two distinct natively folded states. Nat Struct Mol Biol 2004; 11:338–345.PubMedCrossRefGoogle Scholar
  28. 28.
    De Antoni A, Pearson CG, Cimini D et al. The Mad1/Mad2 complex as a template for Mad2 activation in the spindle assembly checkpoint. Curr Biol 2005; 15:214–225.PubMedCrossRefGoogle Scholar
  29. 29.
    Luo X, Fang G, Coldiron M et al. Structure of the Mad2 spindle assembly checkpoint protein and its interaction with Cdc20. Nat Struct Biol 2000; 7:224–229.PubMedCrossRefGoogle Scholar
  30. 30.
    Giet R, Petretti C, Prigent C. Aurora kinases, aneuploidy and cancer, a coincidence or a real link? Trends Cell Biol 2005; 15:241–250.PubMedCrossRefGoogle Scholar
  31. 31.
    Pinsky BA, Kung C, Shokat KM et al. The Ipl1-Aurora protein kinase activates the spindle checkpoint by creating unattached kinetochores. Nat Cell Biol 2006; 8:78–83.PubMedCrossRefGoogle Scholar
  32. 32.
    Hardwick KG, Weiss E, Luca FC et al. Activation of the budding yeast spindle assembly checkpoint without mitotic spindle disruption. Science 1996; 273:953–956.PubMedCrossRefGoogle Scholar
  33. 33.
    Seeley TW, Wang L, Zhen JY. Phosphorylation of human MAD1 by the BUB1 kinase in vitro. Biochem Biophys Res Commun 1999; 257:589–595.PubMedCrossRefGoogle Scholar
  34. 34.
    He X, Jones MH, Winey M et al. Mph1, a member of the Mps1-like family of dual specificity protein kinases, is required for the spindle checkpoint in S. pombe. J Cell Sci 1998; 111:1635–1647.PubMedGoogle Scholar
  35. 35.
    Waters JC, Chen RH, Murray AW et al. Mad2 binding by phosphorylated kinetochores links error detection and checkpoint action in mitosis. Curr Biol 1999; 9:649–652.PubMedCrossRefGoogle Scholar
  36. 36.
    Ahonen LJ, Kallio MJ, Daum JR et al. Polo-like kinase 1 creates the tension-sensing 3F3/2 phosphoepitope and modulates the association of spindle-checkpoint proteins at kinetochores. Curr Biol 2005; 15:1078–1089.PubMedCrossRefGoogle Scholar
  37. 37.
    Wong OK, Fang G. Plx1 is the 3F3/2 kinase responsible for targeting spindle checkpoint proteins to kinetochores. J Cell Biol 2005; 170:709–719.PubMedCrossRefGoogle Scholar
  38. 38.
    Rieder CL, Maiato H. Stuck in division or passing through: what happens when cells cannot satisfy the spindle assembly checkpoint. Dev Cell 2004; 7:637–651.PubMedCrossRefGoogle Scholar
  39. 39.
    Reddy SK, Rape M, Margansky WA et al. Ubiquitination by the anaphase-promoting complex drives spindle checkpoint inactivation. Nature 2007; 446:921–925.PubMedCrossRefGoogle Scholar
  40. 40.
    Stegmeier F, Rape M, Draviam VM et al. Anaphase initiation is regulated by antagonistic ubiquitination and deubiquitination activities. Nature 2007; 446:876–881.PubMedCrossRefGoogle Scholar
  41. 41.
    Howell BJ, McEwen BF, Canman JC et al. Cytoplasmic dynein/dynactin drives kinetochore protein transport to the spindle poles and has a role in mitotic spindle checkpoint inactivation. J Cell Biol 2001; 155:1159–1172.PubMedCrossRefGoogle Scholar
  42. 42.
    Wojcik E, Basto R, Serr M et al. Kinetochore dynein: its dynamics and role in the transport of the Rough deal checkpoint protein. Nat Cell Biol 2001; 3:1001–1007.PubMedCrossRefGoogle Scholar
  43. 43.
    Griffis ER, Stuurman N, Vale RD. Spindly, a novel protein essential for silencing the spindle assembly checkpoint, recruits dynein to the kinetochore. J Cell Biol 2007; 177:1005–1015.PubMedCrossRefGoogle Scholar
  44. 44.
    Shi Q, King RW. Chromosome nondisjunction yields tetraploid rather than aneuploid cells in human cell lines. Nature 2005; 437:1038–1042.PubMedCrossRefGoogle Scholar
  45. 45.
    Boveri T. The origin of malignant tumors. Baltimore, MD: Williams and Wilkins, 1929. Originally published in 1914 as Zur Frage der Entstehung maligner Tumoren.Google Scholar
  46. 46.
    Shackney SE, Smith CA, Miller BW et al. Model for the genetic evolution of human solid tumors. Cancer Res 1989; 49:3344–3354.PubMedGoogle Scholar
  47. 47.
    Andreassen PR, Lohez OD, Lacroix FB et al. Tetraploid state induces p53-dependent arrest of nontransformed mammalian cells in G1. Mol Biol Cell 2001; 12:1315–1328.PubMedGoogle Scholar
  48. 48.
    Galipeau PC, Cowan DS, Sanchez CA et al 17p (p53) allelic losses, 4N (G2/tetraploid) populations and progression to aneuploidy in Barrett’s esophagus. Proc Natl Acad Sci USA 1996; 93:7081–7084.PubMedCrossRefGoogle Scholar
  49. 49.
    Fujiwara T, Bandi M, Nitta M et al. Cytokinesis failure generating tetraploids promotes tumorigenesis in p53-null cells. Nature 2005; 437:1043–1047.PubMedCrossRefGoogle Scholar
  50. 50.
    Sotillo R, Hernando E, Diaz-Rodriguez E et al. Mad2 overexpression promotes aneuploidy and tumorigenesis in mice. Cancer Cell 2007; 11:9–23.PubMedCrossRefGoogle Scholar
  51. 51.
    Mayer VW, Aguilera A. High levels of chromosome instability in polyploids of Saccharomyces cerevisiae. Mutat Res 1990; 231:177–186.PubMedCrossRefGoogle Scholar
  52. 52.
    Andalis AA, Storchova Z, Styles C et al. Defects arising from whole-genome duplications in Saccharomyces cerevisiae. Genetics 2004; 167:1109–1121.PubMedCrossRefGoogle Scholar
  53. 53.
    Storchova Z, Breneman A, Cande J et al. Genome-wide genetic analysis of polyploidy in yeast. Nature 2006; 443:541–547.PubMedCrossRefGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2010

Authors and Affiliations

  1. 1.Radiation Biology Center and Graduate School of BiostudiesKyoto UniversityKyotoJapan

Personalised recommendations