Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
권호 표지
DOI QR코드

DOI QR Code

How Chromosome Mis-Segregation Leads to Cancer: Lessons from BubR1 Mouse Models

  • Lee, Hyunsook (Department of Biological Sciences and the Institute of Molecular Biology and Genetics, Seoul National University)
  • Received : 2014.08.22
  • Accepted : 2014.08.25
  • Published : 2014.10.31
Download PDF
⟨ Previous Next ⟩

Abstract

Alteration in chromosome numbers and structures instigate and foster massive genetic instability. As Boveri has seen a hundred years ago (Boveri, 1914; 2008), aneuploidy is hall-mark of many cancers. However, whether aneuploidy is the cause or the result of cancer is still at debate. The molecular mechanism behind aneuploidy includes the chromosome mis-segregation in mitosis by the compromise of spindle assembly checkpoint (SAC). SAC is an elaborate network of proteins, which monitor that all chromosomes are bipolarly attached with the spindles. Therefore, the weakening of the SAC is the major reason for chromosome number instability, while complete compromise of SAC results in detrimental death, exemplified in natural abortion in embryonic stage. Here, I will review on the recent progress on the understanding of chromosome missegregation and cancer, based on the comparison of different mouse models of BubR1, the core component of SAC.

Keywords

References

  1. Baker, D.J., Jeganathan, K.B., Cameron, J.D., Thompson, M., Juneja, S., Kopecka, A., Kumar, R., Jenkins, R.B., de Groen, P.C., Roche, P., et al. (2004). BubR1 insufficiency causes early onset of aging-associated phenotypes and infertility in mice. Nat. Genet. 36, 744-749. https://doi.org/10.1038/ng1382
  2. Bolanos-Garcia, V.M., and Blundell, T.L. (2011). BUB1 and BUBR1: multifaceted kinases of the cell cycle. Trends Biochem. Sci. 36, 141-150. https://doi.org/10.1016/j.tibs.2010.08.004
  3. Boveri, T. (1914). Zur Frage der Entstehung maligner Tumorer (The origin of malignant tumors). (Jena: Gustav Fischer).
  4. Boveri, T. (2008). Concerning the origin of malignant tumours by Theodor Boveri. Translated and annotated by Henry Harris. J. Cell Sci. 121 (Suppl 1), 1-84.
  5. Burton, J.L., and Solomon, M.J. (2007). Mad3p, a pseudosubstrate inhibitor of APCCdc20 in the spindle assembly checkpoint. Genes Dev. 21, 655-667. https://doi.org/10.1101/gad.1511107
  6. Chan, Y.W., Jeyaprakash, A.A., Nigg, E.A., and Santamaria, A. (2012). Aurora B controls kinetochore-microtubule attachments by inhibiting Ska complex-KMN network interaction. J. Cell Biol. 196, 563-571. https://doi.org/10.1083/jcb.201109001
  7. Chao, W.C., Kulkarni, K., Zhang, Z., Kong, E.H., and Barford, D. (2012). Structure of the mitotic checkpoint complex. Nature 484, 208-213. https://doi.org/10.1038/nature10896
  8. 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, 983-997. https://doi.org/10.1016/j.cell.2006.09.039
  9. Choi, E., Choe, H., Min, J., Choi, J.Y., Kim, J., and Lee, H. (2009). BubR1 acetylation at prometaphase is required for modulating APC/C activity and timing of mitosis. EMBO J. 28, 2077-2089. https://doi.org/10.1038/emboj.2009.123
  10. Choi, E., Park, P.G., Lee, H.O., Lee, Y.K., Kang, G.H., Lee, J.W., Han, W., Lee, H.C., Noh, D.Y., Lekomtsev, S., et al. (2012). BRCA2 fine-tunes the spindle assembly checkpoint through reinforcement of BubR1 acetylation. Dev. Cell 22, 295-308. https://doi.org/10.1016/j.devcel.2012.01.009
  11. de Voer, R.M., Hoogerbrugge, N., and Kuiper, R.P. (2011). Spindleassembly checkpoint and gastrointestinal cancer. N Engl. J. Med. 364, 1279-1280. https://doi.org/10.1056/NEJMc1101053
  12. Dobles, M., Liberal, V., Scott, M.L., Benezra, R., and Sorger, P.K. (2000). Chromosome missegregation and apoptosis in mice lacking the mitotic checkpoint protein Mad2. Cell 101, 635-645. https://doi.org/10.1016/S0092-8674(00)80875-2
  13. Elowe, S., Hummer, S., Uldschmid, A., Li, X., and Nigg, E.A. (2007). Tension-sensitive Plk1 phosphorylation on BubR1 regulates the stability of kinetochore microtubule interactions. Genes Dev. 21, 2205-2219. https://doi.org/10.1101/gad.436007
  14. Elowe, S., Dulla, K., Uldschmid, A., Li, X., Dou, Z., and Nigg, E.A. (2010). Uncoupling of the spindle-checkpoint and chromosomecongression functions of BubR1. J. Cell Sci. 123, 84-94. https://doi.org/10.1242/jcs.056507
  15. Foster, S.A., and Morgan, D.O. (2012). The APC/C subunit Mnd2/Apc15 promotes Cdc20 autoubiquitination and spindle assembly checkpoint inactivation. Mol. Cell 47, 921-932. https://doi.org/10.1016/j.molcel.2012.07.031
  16. Han, J.S., Holland, A.J., Fachinetti, D., Kulukian, A., Cetin, B., and Cleveland, D.W. (2013). Catalytic assembly of the mitotic checkpoint inhibitor BubR1-Cdc20 by a Mad2-induced functional switch in Cdc20. Mol. Cell 51, 92-104. https://doi.org/10.1016/j.molcel.2013.05.019
  17. Huang, H., Hittle, J., Zappacosta, F., Annan, R.S., Hershko, A., and Yen, T.J. (2008). Phosphorylation sites in BubR1 that regulate kinetochore attachment, tension, and mitotic exit. J. Cell Biol. 183, 667-680. https://doi.org/10.1083/jcb.200805163
  18. Jacquemont, S., Boceno, M., Rival, J.M., Mechinaud, F., and David, A. (2002). High risk of malignancy in mosaic variegated aneuploidy syndrome. Am. J. Med. Genet. 109, 17-21; discussion 16. https://doi.org/10.1002/ajmg.10281
  19. Jeganathan, K., Malureanu, L., Baker, D.J., Abraham, S.C., and van Deursen, J.M. (2007). Bub1 mediates cell death in response to chromosome missegregation and acts to suppress spontaneous tumorigenesis. J. Cell Biol. 179, 255-267. https://doi.org/10.1083/jcb.200706015
  20. Kapoor, T.M., Lampson, M.A., Hergert, P., Cameron, L., Cimini, D., Salmon, E.D., McEwen, B.F., and Khodjakov, A. (2006). Chromosomes can congress to the metaphase plate before biorientation. Science 311, 388-391. https://doi.org/10.1126/science.1122142
  21. Kawame, H., Sugio, Y., Fuyama, Y., Hayashi, Y., Suzuki, H., Kurosawa, K., and Maekawa, K. (1999). Syndrome of microcephaly, Dandy-Walker malformation, and Wilms tumor caused by mosaic variegated aneuploidy with premature centromere division (PCD):report of a new case and review of the literature. J. Hum. Genet. 44, 219-224. https://doi.org/10.1007/s100380050147
  22. Kim, Y., Holland, A.J., Lan, W., and Cleveland, D.W. (2010). Aurora kinases and protein phosphatase 1 mediate chromosome congression through regulation of CENP-E. Cell 142, 444-455. https://doi.org/10.1016/j.cell.2010.06.039
  23. 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, 663-676. https://doi.org/10.1016/j.devcel.2007.09.005
  24. Krenn, V., Wehenkel, A., Li, X., Santaguida, S., and Musacchio, A. (2012). Structural analysis reveals features of the spindle checkpoint kinase Bub1-kinetochore subunit Knl1 interaction. J. Cell Biol. 196, 451-467. https://doi.org/10.1083/jcb.201110013
  25. Kruse, T., Zhang, G., Larsen, M.S., Lischetti, T., Streicher, W., Kragh Nielsen, T., Bjorn, S.P., and Nilsson, J. (2013a). Direct binding between BubR1 and B56-PP2A phosphatase complexes regulate mitotic progression. J. Cell Sci. 126, 1086-1092. https://doi.org/10.1242/jcs.122481
  26. Kruse, T., Zhang, G., Larsen, M.S., Lischetti, T., Streicher, W., Nielsen, T.K., Bjorn, S.P., and Nilsson, J. (2013b). Direct binding between BubR1 and B56-PP2A phosphatase complexes regulate mitotic progression. J. Cell Sci.126, 1086-1092. https://doi.org/10.1242/jcs.122481
  27. Lampson, M.A., and Kapoor, T.M. (2005). The human mitotic checkpoint protein BubR1 regulates chromosome-spindle attachments. Nat. Cell Biol. 7, 93-98. https://doi.org/10.1038/ncb1208
  28. Lara-Gonzalez, P., Scott, M.I., Diez, M., Sen, O., and Taylor, S.S. (2011). BubR1 blocks substrate recruitment to the APC/C in a KEN-box-dependent manner. J. Cell Sci. 124, 4332-4345. https://doi.org/10.1242/jcs.094763
  29. Larsen, N.A., Al-Bassam, J., Wei, R.R., and Harrison, S.C. (2007). Structural analysis of Bub3 interactions in the mitotic spindle checkpoint. Proc. Natl. Acad. Sci. USA 104, 1201-1206. https://doi.org/10.1073/pnas.0610358104
  30. Mansfeld, J., Collin, P., Collins, M.O., Choudhary, J.S., and Pines, J. (2011). APC15 drives the turnover of MCC-CDC20 to make the spindle assembly checkpoint responsive to kinetochore attachment. Nat. Cell Biol. 13, 1234-1243. https://doi.org/10.1038/ncb2347
  31. 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. https://doi.org/10.1016/S0092-8674(03)00475-6
  32. Mao, Y., Desai, A., and Cleveland, D.W. (2005). Microtubule capture by CENP-E silences BubR1-dependent mitotic checkpoint signaling. J. Cell Biol. 170, 873-880. https://doi.org/10.1083/jcb.200505040
  33. Matsuura, S., Ito, E., Tauchi, H., Komatsu, K., Ikeuchi, T., and Kajii, T. (2000). Chromosomal instability syndrome of total premature chromatid separation with mosaic variegated aneuploidy is defective in mitotic-spindle checkpoint. Am. J. Hum. Genet. 67, 483-486. https://doi.org/10.1086/303022
  34. Miniowitz-Shemtov, S., Eytan, E., Ganoth, D., Sitry-Shevah, D., Dumin, E., and Hershko, A. (2012). Role of phosphorylation of Cdc20 in p31(comet)-stimulated disassembly of the mitotic checkpoint complex. Proc. Natl. Acad. Sci. USA 109, 8056-8060. https://doi.org/10.1073/pnas.1204081109
  35. Musacchio, A., and Salmon, E.D. (2007). The spindle-assembly checkpoint in space and time. Nat. Rev. Mol. Cell Biol. 8, 379-393. https://doi.org/10.1038/nrm2163
  36. Nilsson, J., Yekezare, M., Minshull, J., and Pines, J. (2008). The APC/C maintains the spindle assembly checkpoint by targeting Cdc20 for destruction. Nat. Cell Biol. 10, 1411-1420. https://doi.org/10.1038/ncb1799
  37. North, B.J., Rosenberg, M.A., Jeganathan, K.B., Hafner, A.V., Michan, S., Dai, J., Baker, D.J., Cen, Y., Wu, L.E., Sauve, A.A., et al. (2014). SIRT2 induces the checkpoint kinase BubR1 to increase lifespan. EMBO J. 33, 1438-1453.
  38. Park, I., Lee, H.O., Choi, E., Lee, Y.K., Kwon, M.S., Min, J., Park, P.G., Lee, S., Kong, Y.Y., Gong, G., et al. (2013). Loss of BubR1 acetylation causes defects in spindle assembly checkpoint signaling and promotes tumor formation. J. Cell Biol. 202, 295-309. https://doi.org/10.1083/jcb.201210099
  39. Rao, C.V., Yang, Y.M., Swamy, M.V., Liu, T., Fang, Y., Mahmood, R., Jhanwar-Uniyal, M., and Dai, W. (2005). Colonic tumorigenesis in BubR1+/-ApcMin/+ compound mutant mice is linked to premature separation of sister chromatids and enhanced genomic instability. Proc. Natl. Acad. Sci. USA 102, 4365-4370. https://doi.org/10.1073/pnas.0407822102
  40. Sudakin, V., Chan, G.K., and Yen, T.J. (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. https://doi.org/10.1083/jcb.200102093
  41. Suijkerbuijk, S.J., van Osch, M.H., Bos, F.L., Hanks, S., Rahman, N., and Kops, G.J. (2010). Molecular causes for BUBR1 dysfunction in the human cancer predisposition syndrome mosaic variegated aneuploidy. Cancer Res. 70, 4891-4900. https://doi.org/10.1158/0008-5472.CAN-09-4319
  42. Suijkerbuijk, S.J., van Dam, T.J., Karagoz, G.E., von Castelmur, E., Hubner, N.C., Duarte, A.M., Vleugel, M., Perrakis, A., Rudiger, S.G., Snel, B., et al. (2012a). The vertebrate mitotic checkpoint protein BUBR1 is an unusual pseudokinase. Dev. Cell 22, 1321-1329. https://doi.org/10.1016/j.devcel.2012.03.009
  43. Suijkerbuijk, S.J., Vleugel, M., Teixeira, A., and Kops, G.J. (2012b). Integration of kinase and phosphatase activities by BUBR1 ensures formation of stable kinetochore-microtubule attachments. Dev. Cell 23, 745-755. https://doi.org/10.1016/j.devcel.2012.09.005
  44. Takeuchi, K., and Fukagawa, T. (2012). Molecular architecture of vertebrate kinetochores. Exp. Cell Res. 318, 1367-1374. https://doi.org/10.1016/j.yexcr.2012.02.016
  45. Tanno, Y., Kitajima, T.S., Honda, T., Ando, Y., Ishiguro, K., and Watanabe, Y. (2010). Phosphorylation of mammalian Sgo2 by Aurora B recruits PP2A and MCAK to centromeres. Genes Dev. 24, 2169-2179. https://doi.org/10.1101/gad.1945310
  46. 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. https://doi.org/10.1083/jcb.142.1.1
  47. Teichner, A., Eytan, E., Sitry-Shevah, D., Miniowitz-Shemtov, S., Dumin, E., Gromis, J., and Hershko, A. (2011). p31comet Promotes disassembly of the mitotic checkpoint complex in an ATPdependent process. Proc. Natl. Acad. Sci. USA 108, 3187-3192. https://doi.org/10.1073/pnas.1100023108
  48. Tian, W., Li, B., Warrington, R., Tomchick, D.R., Yu, H., and Luo, X. (2012). Structural analysis of human Cdc20 supports multisite degron recognition by APC/C. Proc. Natl. Acad. Sci. USA 109, 18419-18424. https://doi.org/10.1073/pnas.1213438109
  49. Uzunova, K., Dye, B.T., Schutz, H., Ladurner, R., Petzold, G., Toyoda, Y., Jarvis, M.A., Brown, N.G., Poser, I., Novatchkova, M., 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. https://doi.org/10.1038/nsmb.2412
  50. Varma, D., and Salmon, E.D. (2012). The KMN protein network--chief conductors of the kinetochore orchestra. J. Cell Sci. 125, 5927-5936. https://doi.org/10.1242/jcs.093724
  51. Watanabe, Y., Khodosevich, K., and Monyer, H. (2014). Dendrite development regulated by the schizophrenia-associated gene FEZ1 involves the ubiquitin proteasome system. Cell Rep. 7, 552-564. https://doi.org/10.1016/j.celrep.2014.03.022
  52. Weaver, B.A., Silk, A.D., Montagna, C., Verdier-Pinard, P., and Cleveland, D.W. (2007). Aneuploidy acts both oncogenically and as a tumor suppressor. Cancer Cell 11, 25-36. https://doi.org/10.1016/j.ccr.2006.12.003
  53. Welburn, J.P., Vleugel, M., Liu, D., Yates, J.R., 3rd, Lampson, M.A., Fukagawa, T., and Cheeseman, I.M. (2010). Aurora B phosphorylates spatially distinct targets to differentially regulate the kinetochore-microtubule interface. Mol. Cell 38, 383-392. https://doi.org/10.1016/j.molcel.2010.02.034
  54. Westhorpe, F.G., Tighe, A., Lara-Gonzalez, P., and Taylor, S.S. (2011). p31comet-mediated extraction of Mad2 from the MCC promotes efficient mitotic exit. J. Cell Sci. 124, 3905-3916. https://doi.org/10.1242/jcs.093286
  55. Wijshake, T., Malureanu, L.A., Baker, D.J., Jeganathan, K.B., van de Sluis, B., and van Deursen, J.M. (2012). Reduced life- and healthspan in mice carrying a mono-allelic BubR1 MVA mutation. PLoS Genet. 8, e1003138. https://doi.org/10.1371/journal.pgen.1003138
  56. Williams, B.R., Prabhu, V.R., Hunter, K.E., Glazier, C.M., Whittaker, C.A., Housman, D.E., and Amon, A. (2008). Aneuploidy affects proliferation and spontaneous immortalization in mammalian cells. Science 322, 703-709. https://doi.org/10.1126/science.1160058
  57. Xu, P., Raetz, E.A., Kitagawa, M., Virshup, D.M., and Lee, S.H. (2013). BUBR1 recruits PP2A via the B56 family of targeting subunits to promote chromosome congression. Biol. Open 2, 479-486. https://doi.org/10.1242/bio.20134051
  58. Yun, M.Y., Kim, S.B., Park, S., Han, C.J., Han, Y.H., Yoon, S.H., Kim, S.H., Kim, C.M., Choi, D.W., Cho, M.H., et al. (2007). Mutation analysis of p31comet gene, a negative regulator of Mad2, in human hepatocellular carcinoma. Exp. Mol. Med. 39, 508-513. https://doi.org/10.1038/emm.2007.56

Cited by

  1. Drosophila models of cancer vol.2, pp.1, 2015, https://doi.org/10.3934/genet.2015.1.97
  2. Revisiting tumour aneuploidy — the place of ploidy assessment in the molecular era vol.13, pp.5, 2015, https://doi.org/10.1038/nrclinonc.2015.208
  3. by Low Concentrations of Chlorpyrifos, Imidacloprid and α-Cypermethrin pp.08936692, 2018, https://doi.org/10.1002/em.22235
  4. Development of a novel HAC-based “gain of signal” quantitative assay for measuring chromosome instability (CIN) in cancer cells vol.7, pp.12, 2016, https://doi.org/10.18632/oncotarget.7854
  5. KDM4C Activity Modulates Cell Proliferation and Chromosome Segregation in Triple-Negative Breast Cancer vol.10, pp.None, 2014, https://doi.org/10.4137/bcbcr.s40182
  6. A Genome-Wide Association Study for Regulators of Micronucleus Formation in Mice vol.6, pp.8, 2016, https://doi.org/10.1534/g3.116.030767
  7. A potential prognostic biomarker SPC24 promotes tumorigenesis and metastasis in lung cancer vol.8, pp.39, 2014, https://doi.org/10.18632/oncotarget.18971
  8. HDAC2/3 binding and deacetylation of BubR1 initiates spindle assembly checkpoint silencing vol.284, pp.23, 2014, https://doi.org/10.1111/febs.14286
  9. SPC24 promotes osteosarcoma progression by increasing EGFR/MAPK signaling vol.8, pp.62, 2014, https://doi.org/10.18632/oncotarget.22167
  10. Elevated DSN1 expression is associated with poor survival in patients with hepatocellular carcinoma vol.81, pp.None, 2014, https://doi.org/10.1016/j.humpath.2018.06.032
  11. Genome-wide DNA copy number analysis and targeted transcriptional analysis of canine histiocytic malignancies identifies diagnostic signatures and highlights disruption of spindle assembly complex vol.27, pp.3, 2019, https://doi.org/10.1007/s10577-019-09606-0
  12. Spindle assembly checkpoint gene BUB1B is essential in breast cancer cell survival vol.185, pp.2, 2014, https://doi.org/10.1007/s10549-020-05962-2