Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi


  • Adeel Asghar
  • Sabine EloweEmail author
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101546



Related Molecules in the Encyclopedia

Historical Background

Bub1 was originally discovered as a gene required for cell cycle arrest during mitosis in response to the microtubule depolymerizing drug benzimidazole in the model organism Saccharomyces cerevisiae (Hoyt et al. 1991). Mutant yeast were unable to arrest and inhibit the budding process at the end of mitosis, a marker for cell cycle progression, hence the name Budding Uninhibited by Benzimidazole 1 (BUB1). Through its capacity to contribute to mitotic arrest, BUB1 functions as an integral component of the spindle assembly checkpoint (SAC), a surveillance mechanism that delays mitotic progression until all kinetochores are properly attached to microtubules, and aligned at the spindle equator in metaphase. Since its original discovery in budding yeast, a SAC function for BUB1 has been verified in all model organisms studied to date (reviewed in (Elowe 2011...

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  1. Asghar A, Lajeunesse A, Dulla K, Combes G, Thebault P, Nigg EA, et al. Bub1 autophosphorylation feeds back to regulate kinetochore docking and promote localized substrate phosphorylation. Nat Commun. 2015;6:8364.  https://doi.org/10.1038/ncomms9364.CrossRefPubMedPubMedCentralGoogle Scholar
  2. Baron AP, von Schubert C, Cubizolles F, Siemeister G, Hitchcock M, Mengel A, et al. Probing the catalytic functions of Bub1 kinase using the small molecule inhibitors BAY-320 and BAY-524. Elife. 2016;5.  https://doi.org/10.7554/eLife.12187.
  3. Basu J, Logarinho E, Herrmann S, Bousbaa H, Li Z, Chan GK, et al. Localization of the Drosophila checkpoint control protein Bub3 to the kinetochore requires Bub1 but not Zw10 or Rod. Chromosoma. 1998;107:376–85.PubMedPubMedCentralCrossRefGoogle Scholar
  4. Bernard P, Hardwick K, Javerzat JP. Fission yeast bub1 is a mitotic centromere protein essential for the spindle checkpoint and the preservation of correct ploidy through mitosis. J Cell Biol. 1998;143:1775–87.PubMedPubMedCentralCrossRefGoogle Scholar
  5. Bokros M, Gravenmier C, Jin F, Richmond D, Wang Y. Fin1-PP1 helps clear spindle assembly checkpoint protein Bub1 from kinetochores in anaphase. Cell Rep. 2016;14:1074–85.  https://doi.org/10.1016/j.celrep.2016.01.007.CrossRefPubMedPubMedCentralGoogle Scholar
  6. Bolanos-Garcia VM, Blundell TL. BUB1 and BUBR1: multifaceted kinases of the cell cycle. Trends Biochem Sci. 2011;36:141–50.  https://doi.org/10.1016/j.tibs.2010.08.004.CrossRefPubMedPubMedCentralGoogle Scholar
  7. Cahill DP, Lengauer C, Yu J, Riggins GJ, Willson JK, Markowitz SD, et al. Mutations of mitotic checkpoint genes in human cancers. Nature. 1998;392:300–3.  https://doi.org/10.1038/32688.CrossRefPubMedCentralPubMedGoogle Scholar
  8. Cahill DP, da Costa LT, Carson-Walter EB, Kinzler KW, Vogelstein B, Lengauer C. Characterization of MAD2B and other mitotic spindle checkpoint genes. Genomics. 1999;58:181–7.  https://doi.org/10.1006/geno.1999.5831.CrossRefPubMedCentralPubMedGoogle Scholar
  9. Cheeseman IM. The kinetochore. Cold Spring Harb Perspect Biol. 2014;6:a015826.  https://doi.org/10.1101/cshperspect.a015826.CrossRefPubMedPubMedCentralGoogle Scholar
  10. Di Fiore B, Davey NE, Hagting A, Izawa D, Mansfeld J, Gibson TJ, et al. The ABBA motif binds APC/C activators and is shared by APC/C substrates and regulators. Dev Cell. 2015;32:358–72.  https://doi.org/10.1016/j.devcel.2015.01.003.CrossRefPubMedPubMedCentralGoogle Scholar
  11. Elowe S. Bub1 and BubR1: at the interface between chromosome attachment and the spindle checkpoint. Mol Cell Biol. 2011;31:3085–93.  https://doi.org/10.1128/MCB.05326-11.CrossRefPubMedPubMedCentralGoogle Scholar
  12. Encalada SE, Willis J, Lyczak R, Bowerman B. A spindle checkpoint functions during mitosis in the early Caenorhabditis elegans embryo. Mol Biol Cell. 2005;16:1056–70.  https://doi.org/10.1091/mbc.E04-08-0712.CrossRefPubMedPubMedCentralGoogle Scholar
  13. Espert A, Uluocak P, Bastos RN, Mangat D, Graab P, Gruneberg U. PP2A-B56 opposes Mps1 phosphorylation of Knl1 and thereby promotes spindle assembly checkpoint silencing. J Cell Biol. 2014;206:833–42.  https://doi.org/10.1083/jcb.201406109.CrossRefPubMedPubMedCentralGoogle Scholar
  14. Espeut J, Lara-Gonzalez P, Sassine M, Shiau AK, Desai A, Abrieu A. Natural loss of Mps1 kinase in nematodes uncovers a role for polo-like kinase 1 in spindle checkpoint initiation. Cell Rep. 2015;12:58–65.  https://doi.org/10.1016/j.celrep.2015.05.039.CrossRefPubMedPubMedCentralGoogle Scholar
  15. Fernius J, Hardwick KG. Bub1 kinase targets Sgo1 to ensure efficient chromosome biorientation in budding yeast mitosis. PLoS Genet. 2007;3:e213.  https://doi.org/10.1371/journal.pgen.0030213.CrossRefPubMedPubMedCentralGoogle Scholar
  16. Gordon DJ, Resio B, Pellman D. Causes and consequences of aneuploidy in cancer. Nat Rev Genet. 2012;13:189–203.  https://doi.org/10.1038/nrg3123.CrossRefPubMedCentralPubMedGoogle Scholar
  17. Howell BJ, Moree B, Farrar EM, Stewart S, Fang G, Salmon ED. Spindle checkpoint protein dynamics at kinetochores in living cells. Curr Biol. 2004;14:953–64.  https://doi.org/10.1016/j.cub.2004.05.053.CrossRefPubMedCentralPubMedGoogle Scholar
  18. Hoyt MA, Totis L, Roberts BT. S. cerevisiae genes required for cell cycle arrest in response to loss of microtubule function. Cell. 1991;66:507–17.PubMedPubMedCentralCrossRefGoogle Scholar
  19. Jia L, Li B, Yu H. The Bub1-Plk1 kinase complex promotes spindle checkpoint signalling through Cdc20 phosphorylation. Nat Commun. 2016;7:10818.  https://doi.org/10.1038/ncomms10818.CrossRefPubMedPubMedCentralGoogle Scholar
  20. Johnson VL, Scott MI, Holt SV, Hussein D, Taylor SS. Bub1 is required for kinetochore localization of BubR1, Cenp-E, Cenp-F and Mad2, and chromosome congression. J Cell Sci. 2004;117:1577–89.  https://doi.org/10.1242/jcs.01006.CrossRefPubMedCentralPubMedGoogle Scholar
  21. Kang J, Yang M, Li B, Qi W, Zhang C, Shokat KM, et al. Structure and substrate recruitment of the human spindle checkpoint kinase Bub1. Mol Cell. 2008;32:394–405.  https://doi.org/10.1016/j.molcel.2008.09.017.CrossRefPubMedPubMedCentralGoogle Scholar
  22. Kawashima SA, Yamagishi Y, Honda T, Ishiguro K, Watanabe Y. Phosphorylation of H2A by Bub1 prevents chromosomal instability through localizing shugoshin. Science. 2010;327:172–7.  https://doi.org/10.1126/science.1180189.CrossRefPubMedCentralPubMedGoogle Scholar
  23. Kim S, Sun H, Tomchick DR, Yu H, Luo X. Structure of human Mad1 C-terminal domain reveals its involvement in kinetochore targeting. Proc Natl Acad Sci USA. 2012;109:6549–54.  https://doi.org/10.1073/pnas.1118210109.CrossRefPubMedPubMedCentralGoogle Scholar
  24. Kitajima TS, Sakuno T, Ishiguro K, Iemura S, Natsume T, Kawashima SA, et al. Shugoshin collaborates with protein phosphatase 2A to protect cohesin. Nature. 2006;441:46–52.  https://doi.org/10.1038/nature04663.CrossRefPubMedCentralPubMedGoogle Scholar
  25. Kiyomitsu T, Obuse C, Yanagida M. Human Blinkin/AF15q14 is required for chromosome alignment and the mitotic checkpoint through direct interaction with Bub1 and BubR1. Dev Cell. 2007;13:663–76.  https://doi.org/10.1016/j.devcel.2007.09.005.CrossRefPubMedCentralPubMedGoogle Scholar
  26. Klebig C, Korinth D, Meraldi P. Bub1 regulates chromosome segregation in a kinetochore-independent manner. J Cell Biol. 2009;185:841–58.  https://doi.org/10.1083/jcb.200902128.CrossRefPubMedPubMedCentralGoogle Scholar
  27. Krenn V, Wehenkel A, Li X, Santaguida S, Musacchio A. Structural analysis reveals features of the spindle checkpoint kinase Bub1-kinetochore subunit Knl1 interaction. J Cell Biol. 2012;196:451–67.  https://doi.org/10.1083/jcb.201110013.CrossRefPubMedPubMedCentralGoogle Scholar
  28. Krenn V, Overlack K, Primorac I, van Gerwen S, Musacchio A. KI motifs of human Knl1 enhance assembly of comprehensive spindle checkpoint complexes around MELT repeats. Curr Biol. 2014;24:29–39.  https://doi.org/10.1016/j.cub.2013.11.046.CrossRefPubMedCentralPubMedGoogle Scholar
  29. Lee S, Thebault P, Freschi L, Beaufils S, Blundell TL, Landry CR, et al. Characterization of spindle checkpoint kinase Mps1 reveals domain with functional and structural similarities to tetratricopeptide repeat motifs of Bub1 and BubR1 checkpoint kinases. J Biol Chem. 2012;287:5988–6001.  https://doi.org/10.1074/jbc.M111.307355.CrossRefPubMedCentralPubMedGoogle Scholar
  30. Lin Z, Jia L, Tomchick DR, Luo X, Yu H. Substrate-specific activation of the mitotic kinase Bub1 through intramolecular autophosphorylation and kinetochore targeting. Structure. 2014;22:1616–27.  https://doi.org/10.1016/j.str.2014.08.020.CrossRefPubMedCentralPubMedGoogle Scholar
  31. Lischetti T, Zhang G, Sedgwick GG, Bolanos-Garcia VM, Nilsson J. The internal Cdc20 binding site in BubR1 facilitates both spindle assembly checkpoint signalling and silencing. Nat Commun. 2014;5:5563.  https://doi.org/10.1038/ncomms6563.CrossRefPubMedCentralPubMedGoogle Scholar
  32. Liu H, Jia L, Yu H. Phospho-H2A and cohesin specify distinct tension-regulated Sgo1 pools at kinetochores and inner centromeres. Curr Biol. 2013;23:1927–33.  https://doi.org/10.1016/j.cub.2013.07.078.CrossRefPubMedCentralPubMedGoogle Scholar
  33. Logarinho E, Resende T, Torres C, Bousbaa H. The human spindle assembly checkpoint protein Bub3 is required for the establishment of efficient kinetochore-microtubule attachments. Mol Biol Cell. 2008;19:1798–813.  https://doi.org/10.1091/mbc.E07-07-0633.CrossRefPubMedPubMedCentralGoogle Scholar
  34. London N, Ceto S, Ranish JA, Biggins S. Phosphoregulation of Spc105 by Mps1 and PP1 regulates Bub1 localization to kinetochores. Curr Biol. 2012;22:900–6.  https://doi.org/10.1016/j.cub.2012.03.052.CrossRefPubMedPubMedCentralGoogle Scholar
  35. Nijenhuis W, Vallardi G, Teixeira A, Kops GJ, Saurin AT. Negative feedback at kinetochores underlies a responsive spindle checkpoint signal. Nat Cell Biol. 2014;16:1257–64.  https://doi.org/10.1038/ncb3065.CrossRefPubMedCentralPubMedGoogle Scholar
  36. Nyati S, Schinske-Sebolt K, Pitchiaya S, Chekhovskiy K, Chator A, Chaudhry N, et al. The kinase activity of the Ser/Thr kinase BUB1 promotes TGF-beta signaling. Sci Signal. 2015;8:ra1.  https://doi.org/10.1126/scisignal.2005379.CrossRefPubMedPubMedCentralGoogle Scholar
  37. Overlack K, Primorac I, Vleugel M, Krenn V, Maffini S, Hoffmann I, et al. A molecular basis for the differential roles of Bub1 and BubR1 in the spindle assembly checkpoint. Elife. 2015;4:e05269.  https://doi.org/10.7554/eLife.05269.CrossRefPubMedPubMedCentralGoogle Scholar
  38. Perera D, Taylor SS. Sgo1 establishes the centromeric cohesion protection mechanism in G2 before subsequent Bub1-dependent recruitment in mitosis. J Cell Sci. 2010;123:653–9.  https://doi.org/10.1242/jcs.059501.CrossRefPubMedCentralPubMedGoogle Scholar
  39. Primorac I, Weir JR, Chiroli E, Gross F, Hoffmann I, van Gerwen S, et al. Bub3 reads phosphorylated MELT repeats to promote spindle assembly checkpoint signaling. Elife. 2013;2:e01030.  https://doi.org/10.7554/eLife.01030.CrossRefPubMedPubMedCentralGoogle Scholar
  40. Qi W, Yu H. KEN-box-dependent degradation of the Bub1 spindle checkpoint kinase by the anaphase-promoting complex/cyclosome. J Biol Chem. 2007;282:3672–9.  https://doi.org/10.1074/jbc.M609376200.CrossRefPubMedCentralPubMedGoogle Scholar
  41. Ricke RM, Jeganathan KB, van Deursen JM. Bub1 overexpression induces aneuploidy and tumor formation through Aurora B kinase hyperactivation. J Cell Biol. 2011;193:1049–64.  https://doi.org/10.1083/jcb.201012035.CrossRefPubMedPubMedCentralGoogle Scholar
  42. Ricke RM, Jeganathan KB, Malureanu L, Harrison AM, van Deursen JM. Bub1 kinase activity drives error correction and mitotic checkpoint control but not tumor suppression. J Cell Biol. 2012;199:931–49.  https://doi.org/10.1083/jcb.201205115.CrossRefPubMedPubMedCentralGoogle Scholar
  43. Rischitor PE, May KM, Hardwick KG. Bub1 is a fission yeast kinetochore scaffold protein, and is sufficient to recruit other spindle checkpoint proteins to ectopic sites on chromosomes. PLoS One. 2007;2:e1342.  https://doi.org/10.1371/journal.pone.0001342.CrossRefPubMedPubMedCentralGoogle Scholar
  44. Roberts BT, Farr KA, Hoyt MA. The Saccharomyces cerevisiae checkpoint gene BUB1 encodes a novel protein kinase. Mol Cell Biol. 1994;14:8282–91.PubMedPubMedCentralCrossRefGoogle Scholar
  45. Rosenberg JS, Cross FR, Funabiki H. KNL1/Spc105 recruits PP1 to silence the spindle assembly checkpoint. Curr Biol. 2011;21:942–7.  https://doi.org/10.1016/j.cub.2011.04.011.CrossRefPubMedPubMedCentralGoogle Scholar
  46. Schvartzman JM, Sotillo R, Benezra R. Mitotic chromosomal instability and cancer: mouse modelling of the human disease. Nat Rev Cancer. 2010;10:102–15.  https://doi.org/10.1038/nrc2781.CrossRefPubMedPubMedCentralGoogle Scholar
  47. Shah JV, Botvinick E, Bonday Z, Furnari F, Berns M, Cleveland DW. Dynamics of centromere and kinetochore proteins; implications for checkpoint signaling and silencing. Curr Biol. 2004;14:942–52.  https://doi.org/10.1016/j.cub.2004.05.046.CrossRefPubMedCentralPubMedGoogle Scholar
  48. Sharp-Baker H, Chen RH. Spindle checkpoint protein Bub1 is required for kinetochore localization of Mad1, Mad2, Bub3, and CENP-E, independently of its kinase activity. J Cell Biol. 2001;153:1239–50.PubMedPubMedCentralCrossRefGoogle Scholar
  49. Shepperd LA, Meadows JC, Sochaj AM, Lancaster TC, Zou J, Buttrick GJ, et al. Phosphodependent recruitment of Bub1 and Bub3 to Spc7/KNL1 by Mph1 kinase maintains the spindle checkpoint. Curr Biol. 2012;22:891–9.  https://doi.org/10.1016/j.cub.2012.03.051.CrossRefPubMedPubMedCentralGoogle Scholar
  50. Silva PM, Reis RM, Bolanos-Garcia VM, Florindo C, Tavares AA, Bousbaa H. Dynein-dependent transport of spindle assembly checkpoint proteins off kinetochores toward spindle poles. FEBS Lett. 2014;588:3265–73.  https://doi.org/10.1016/j.febslet.2014.07.011.CrossRefPubMedCentralPubMedGoogle Scholar
  51. Suijkerbuijk SJ, Vleugel M, Teixeira A, Kops GJ. Integration of kinase and phosphatase activities by BUBR1 ensures formation of stable kinetochore-microtubule attachments. Dev Cell. 2012;23:745–55.  https://doi.org/10.1016/j.devcel.2012.09.005.CrossRefPubMedCentralPubMedGoogle Scholar
  52. Tang Z, Shu H, Oncel D, Chen S, Yu H. Phosphorylation of Cdc20 by Bub1 provides a catalytic mechanism for APC/C inhibition by the spindle checkpoint. Mol Cell. 2004;16:387–97.  https://doi.org/10.1016/j.molcel.2004.09.031.CrossRefPubMedCentralPubMedGoogle Scholar
  53. Tang Z, Shu H, Qi W, Mahmood NA, Mumby MC, Yu H. PP2A is required for centromeric localization of Sgo1 and proper chromosome segregation. Dev Cell. 2006;10:575–85.  https://doi.org/10.1016/j.devcel.2006.03.010.CrossRefPubMedCentralPubMedGoogle Scholar
  54. Taylor SS, McKeon F. Kinetochore localization of murine Bub1 is required for normal mitotic timing and checkpoint response to spindle damage. Cell. 1997;89:727–35.CrossRefPubMedGoogle Scholar
  55. Taylor SS, Ha E, McKeon F. The human homologue of Bub3 is required for kinetochore localization of Bub1 and a Mad3/Bub1-related protein kinase. J Cell Biol. 1998;142:1–11.PubMedPubMedCentralCrossRefGoogle Scholar
  56. Vanoosthuyse V, Hardwick KG. A novel protein phosphatase 1-dependent spindle checkpoint silencing mechanism. Curr Biol. 2009;19:1176–81.  https://doi.org/10.1016/j.cub.2009.05.060.CrossRefPubMedPubMedCentralGoogle Scholar
  57. Vanoosthuyse V, Valsdottir R, Javerzat JP, Hardwick KG. Kinetochore targeting of fission yeast Mad and Bub proteins is essential for spindle checkpoint function but not for all chromosome segregation roles of Bub1p. Mol Cell Biol. 2004;24:9786–801.  https://doi.org/10.1128/MCB.24.22.9786-9801.2004.CrossRefPubMedPubMedCentralGoogle Scholar
  58. Vleugel M, Tromer E, Omerzu M, Groenewold V, Nijenhuis W, Snel B, et al. Arrayed BUB recruitment modules in the kinetochore scaffold KNL1 promote accurate chromosome segregation. J Cell Biol. 2013;203:943–55.  https://doi.org/10.1083/jcb.201307016.CrossRefPubMedPubMedCentralGoogle Scholar
  59. Vleugel M, Hoek TA, Tromer E, Sliedrecht T, Groenewold V, Omerzu M, et al. Dissecting the roles of human BUB1 in the spindle assembly checkpoint. J Cell Sci. 2015;128:2975–82.  https://doi.org/10.1242/jcs.169821.CrossRefPubMedGoogle Scholar
  60. von Schubert C, Cubizolles F, Bracher JM, Sliedrecht T, Kops GJ, Nigg EA. Plk1 and Mps1 cooperatively regulate the spindle assembly checkpoint in human cells. Cell Rep. 2015;12:66–78.  https://doi.org/10.1016/j.celrep.2015.06.007.CrossRefGoogle Scholar
  61. Wang Z, Katsaros D, Shen Y, Fu Y, Canuto EM, Benedetto C, et al. Biological and clinical significance of MAD2L1 and BUB1, genes frequently appearing in expression signatures for breast cancer prognosis. PLoS One. 2015;10:e0136246.  https://doi.org/10.1371/journal.pone.0136246.CrossRefPubMedPubMedCentralGoogle Scholar
  62. Weaver BA, Cleveland DW. Does aneuploidy cause cancer? Curr Opin Cell Biol. 2006;18:658–67.  https://doi.org/10.1016/j.ceb.2006.10.002.CrossRefPubMedGoogle Scholar
  63. Weiss A, Attisano L. The TGFbeta superfamily signaling pathway. Wiley Interdiscip Rev Dev Biol. 2013;2:47–63.  https://doi.org/10.1002/wdev.86.CrossRefPubMedGoogle Scholar
  64. Zhang G, Lischetti T, Hayward DG, Nilsson J. Distinct domains in Bub1 localize RZZ and BubR1 to kinetochores to regulate the checkpoint. Nat Commun. 2015;6:7162.  https://doi.org/10.1038/ncomms8162.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Centre de recherche du CHUM(Notre-Dame) et Institut du Cancer de MontréalQuébecCanada
  2. 2.Axe of Reproduction, Mother and Youth HealthCentre de recherche du Centre Hospitalier Universitaire de QuébecQuébecCanada
  3. 3.The Department of Pediatrics, Faculty of MedicineUniversité LavalQuébec CityCanada