1932

Abstract

Chromosomal instability (CIN), the persistent inability of a cell to faithfully segregate its genome, is a feature of many cancer cells. It stands to reason that CIN enables the acquisition of multiple cancer hallmarks; however, there is a growing body of evidence suggesting that CIN impairs cellular fitness and prevents neoplastic transformation. Here, we suggest a new perspective to reconcile this apparent paradox and share an unexpected link between aneuploidy and aging that was discovered through attempts to investigate the CIN-cancer relationship. Additionally, we provide a comprehensive overview of the function and regulation of the anaphase-promoting complex, an E3 ubiquitin ligase that mediates high-fidelity chromosome segregation, and describe the mechanisms that lead to whole-chromosome gain or loss. With this review, we aim to expand our understanding of the role of CIN in cancer and aging with the long-term objective of harnessing this information for the advancement of patient care.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-genet-120215-035303
2016-11-23
2024-06-21
Loading full text...

Full text loading...

/deliver/fulltext/genet/50/1/annurev-genet-120215-035303.html?itemId=/content/journals/10.1146/annurev-genet-120215-035303&mimeType=html&fmt=ahah

Literature Cited

  1. Baker DJ, Dawlaty MM, Wijshake T, Jeganathan KB, Malureanu L. 1.  et al. 2013. Increased expression of BubR1 protects against aneuploidy and cancer and extends healthy lifespan. Nat. Cell Biol. 15:96–102 [Google Scholar]
  2. Baker DJ, Jeganathan KB, Cameron JD, Thompson M, Juneja S. 2.  et al. 2004. BubR1 insufficiency causes early onset of aging-associated phenotypes and infertility in mice. Nat. Genet. 36:744–49 [Google Scholar]
  3. Baker DJ, Jeganathan KB, Malureanu L, Perez-Terzic C, Terzic A, van Deursen JM. 3.  2006. Early aging-associated phenotypes in Bub3/Rae1 haploinsufficient mice. J. Cell Biol. 172:529–40 [Google Scholar]
  4. Baker DJ, Jin F, Jeganathan KB, van Deursen JM. 4.  2009. Whole chromosome instability caused by Bub1 insufficiency drives tumorigenesis through tumor suppressor gene loss of heterozygosity. Cancer Cell 16:475–86 [Google Scholar]
  5. Baker DJ, Perez-Terzic C, Jin F, Pitel K, Niederlander NJ. 5.  et al. 2008. Opposing roles for p16Ink4a and p19Arf in senescence and ageing caused by BubR1 insufficiency. Nat. Cell Biol. 10:825–36 [Google Scholar]
  6. Baker DJ, Wijshake T, Tchkonia T, LeBrasseur NK, Childs BG. 6.  et al. 2011. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479:232–36 [Google Scholar]
  7. Bakhoum SF, Genovese G, Compton DA. 7.  2009. Deviant kinetochore microtubule dynamics underlie chromosomal instability. Curr. Biol. 19:1937–42 [Google Scholar]
  8. Bakhoum SF, Thompson SL, Manning AL, Compton DA. 8.  2009. Genome stability is ensured by temporal control of kinetochore-microtubule dynamics. Nat. Cell Biol. 11:27–35 [Google Scholar]
  9. Birkbak NJ, Eklund AC, Li Q, McClelland SE, Endesfelder D. 9.  et al. 2011. Paradoxical relationship between chromosomal instability and survival outcome in cancer. Cancer Res. 71:3447–52 [Google Scholar]
  10. Boveri T. 10.  2008. Concerning the origin of malignant tumours by Theodor Boveri. Translated and annotated by Henry Harris. J. Cell Sci. 121:Suppl. 11–84 [Google Scholar]
  11. Brown NG, Watson ER, Weissmann F, Jarvis MA, VanderLinden R. 11.  et al. 2014. Mechanism of polyubiquitination by human anaphase-promoting complex: RING repurposing for ubiquitin chain assembly. Mol. Cell 56:246–60 [Google Scholar]
  12. Chang L, Zhang Z, Yang J, McLaughlin SH, Barford D. 12.  2014. Molecular architecture and mechanism of the anaphase-promoting complex. Nature 513:388–93 [Google Scholar]
  13. Chao WC, Kulkarni K, Zhang Z, Kong EH, Barford D. 13.  2012. Structure of the mitotic checkpoint complex. Nature 484:208–13 [Google Scholar]
  14. Cheeseman IM, Anderson S, Jwa M, Green EM, Kang J. 14.  et al. 2002. Phospho-regulation of kinetochore-microtubule attachments by the Aurora kinase Ipl1p. Cell 111:163–72 [Google Scholar]
  15. Cheeseman IM, Chappie JS, Wilson-Kubalek EM, Desai A. 15.  2006. The conserved KMN network constitutes the core microtubule-binding site of the kinetochore. Cell 127:983–97 [Google Scholar]
  16. Chen RH, Shevchenko A, Mann M, Murray AW. 16.  1998. Spindle checkpoint protein Xmad1 recruits Xmad2 to unattached kinetochores. J. Cell Biol. 143:283–95 [Google Scholar]
  17. Chen RH, Waters JC, Salmon ED, Murray AW. 17.  1996. Association of spindle assembly checkpoint component XMAD2 with unattached kinetochores. Science 274:242–46 [Google Scholar]
  18. Cimini D, Cameron LA, Salmon ED. 18.  2004. Anaphase spindle mechanics prevent mis-segregation of merotelically oriented chromosomes. Curr. Biol. 14:2149–55 [Google Scholar]
  19. Cimini D, Howell B, Maddox P, Khodjakov A, Degrassi F, Salmon ED. 19.  2001. Merotelic kinetochore orientation is a major mechanism of aneuploidy in mitotic mammalian tissue cells. J. Cell Biol. 153:517–27 [Google Scholar]
  20. Cimini D, Wan X, Hirel CB, Salmon ED. 20.  2006. Aurora kinase promotes turnover of kinetochore microtubules to reduce chromosome segregation errors. Curr. Biol. 16:1711–18 [Google Scholar]
  21. Clute P, Pines J. 21.  1999. Temporal and spatial control of cyclin B1 destruction in metaphase. Nat. Cell Biol. 1:82–87 [Google Scholar]
  22. Cohen-Fix O, Peters JM, Kirschner MW, Koshland D. 22.  1996. Anaphase initiation in Saccharomyces cerevisiae is controlled by the APC-dependent degradation of the anaphase inhibitor Pds1p. Genes Dev. 10:3081–93 [Google Scholar]
  23. da Fonseca PC, Kong EH, Zhang Z, Schreiber A, Williams MA. 23.  et al. 2011. Structures of APC/C(Cdh1) with substrates identify Cdh1 and Apc10 as the D-box co-receptor. Nature 470:274–78 [Google Scholar]
  24. De Antoni A, Pearson CG, Cimini D, Canman JC, Sala V. 24.  et al. 2005. The Mad1/Mad2 complex as a template for Mad2 activation in the spindle assembly checkpoint. Curr. Biol. 15:214–25 [Google Scholar]
  25. Di Fiore B, Pines J. 25.  2007. Emi1 is needed to couple DNA replication with mitosis but does not regulate activation of the mitotic APC/C. J. Cell Biol. 177:425–37 [Google Scholar]
  26. Duijf PH, Schultz N, Benezra R. 26.  2013. Cancer cells preferentially lose small chromosomes. Int. J. Cancer. 132:2316–26 [Google Scholar]
  27. Ertych N, Stolz A, Stenzinger A, Weichert W, Kaulfuss S. 27.  et al. 2014. Increased microtubule assembly rates influence chromosomal instability in colorectal cancer cells. Nat. Cell Biol. 16:779–91 [Google Scholar]
  28. Fang G. 28.  2002. Checkpoint protein BubR1 acts synergistically with Mad2 to inhibit anaphase-promoting complex. Mol. Biol. Cell 13:755–66 [Google Scholar]
  29. Fearon ER, Vogelstein B. 29.  1990. A genetic model for colorectal tumorigenesis. Cell 61:759–67 [Google Scholar]
  30. Foster SA, Morgan DO. 30.  2012. The APC/C subunit Mnd2/Apc15 promotes Cdc20 autoubiquitination and spindle assembly checkpoint inactivation. Mol. Cell 47:921–32 [Google Scholar]
  31. Frye JJ, Brown NG, Petzold G, Watson ER, Grace CR. 31.  et al. 2013. Electron microscopy structure of human APC/C(CDH1)-EMI1 reveals multimodal mechanism of E3 ligase shutdown. Nat. Struct. Mol. Biol. 20:827–35 [Google Scholar]
  32. Ganem NJ, Godinho SA, Pellman D. 32.  2009. A mechanism linking extra centrosomes to chromosomal instability. Nature 460:278–82 [Google Scholar]
  33. Ganem NJ, Pellman D. 33.  2012. Linking abnormal mitosis to the acquisition of DNA damage. J. Cell Biol. 199:871–81 [Google Scholar]
  34. Garnett MJ, Mansfeld J, Godwin C, Matsusaka T, Wu J. 34.  et al. 2009. UBE2S elongates ubiquitin chains on APC/C substrates to promote mitotic exit. Nat. Cell Biol. 11:1363–69 [Google Scholar]
  35. Gautier J, Minshull J, Lohka M, Glotzer M, Hunt T, Maller JL. 35.  1990. Cyclin is a component of maturation-promoting factor from Xenopus. Cell 60:487–94 [Google Scholar]
  36. Gavet O, Pines J. 36.  2010. Progressive activation of cyclinB1-Cdk1 coordinates entry to mitosis. Dev. Cell 18:533–43 [Google Scholar]
  37. Godek KM, Kabeche L, Compton DA. 37.  2015. Regulation of kinetochore-microtubule attachments through homeostatic control during mitosis. Nat. Rev. Mol. Cell Biol. 16:57–64 [Google Scholar]
  38. Gonczy P. 38.  2012. Towards a molecular architecture of centriole assembly. Nat. Rev. Mol. Cell Biol. 13:425–35 [Google Scholar]
  39. Gordon DJ, Resio B, Pellman D. 39.  2012. Causes and consequences of aneuploidy in cancer. Nat. Rev. Genet. 13:189–203 [Google Scholar]
  40. Gregan J, Polakova S, Zhang L, Tolic-Norrelykke IM, Cimini D. 40.  2011. Merotelic kinetochore attachment: causes and effects. Trends Cell Biol. 21:374–81 [Google Scholar]
  41. Haarhuis JH, Elbatsh AM, Rowland BD. 41.  2014. Cohesin and its regulation: on the logic of X-shaped chromosomes. Dev. Cell 31:7–18 [Google Scholar]
  42. Haering CH, Farcas AM, Arumugam P, Metson J, Nasmyth K. 42.  2008. The cohesin ring concatenates sister DNA molecules. Nature 454:297–301 [Google Scholar]
  43. Haering CH, Lowe J, Hochwagen A, Nasmyth K. 43.  2002. Molecular architecture of SMC proteins and the yeast cohesin complex. Mol. Cell 9:773–88 [Google Scholar]
  44. Hagting A, Den Elzen N, Vodermaier HC, Waizenegger IC, Peters JM, Pines J. 44.  2002. Human securin proteolysis is controlled by the spindle checkpoint and reveals when the APC/C switches from activation by Cdc20 to Cdh1. J. Cell Biol. 157:1125–37 [Google Scholar]
  45. Han JS, Holland AJ, Fachinetti D, Kulukian A, Cetin B, Cleveland DW. 45.  2013. Catalytic assembly of the mitotic checkpoint inhibitor BubR1-Cdc20 by a Mad2-induced functional switch in Cdc20. Mol. Cell 51:92–104 [Google Scholar]
  46. Hanahan D, Weinberg RA. 46.  2011. Hallmarks of cancer: the next generation. Cell 144:646–74 [Google Scholar]
  47. Hanks S, Coleman K, Reid S, Plaja A, Firth H. 47.  et al. 2004. Constitutional aneuploidy and cancer predisposition caused by biallelic mutations in BUB1B. Nat. Genet. 36:1159–61 [Google Scholar]
  48. Hansen DV, Loktev AV, Ban KH, Jackson PK. 48.  2004. Plk1 regulates activation of the anaphase promoting complex by phosphorylating and triggering SCFβTrCP-dependent destruction of the APC inhibitor Emi1. Mol. Biol. Cell 15:5623–34 [Google Scholar]
  49. Hauf S, Waizenegger IC, Peters JM. 49.  2001. Cohesin cleavage by separase required for anaphase and cytokinesis in human cells. Science 293:1320–23 [Google Scholar]
  50. He J, Chao WC, Zhang Z, Yang J, Cronin N, Barford D. 50.  2013. Insights into degron recognition by APC/C coactivators from the structure of an Acm1-Cdh1 complex. Mol. Cell 50:649–60 [Google Scholar]
  51. Herzog F, Primorac I, Dube P, Lenart P, Sander B. 51.  et al. 2009. Structure of the anaphase-promoting complex/cyclosome interacting with a mitotic checkpoint complex. Science 323:1477–81 [Google Scholar]
  52. Holland AJ, Lan W, Cleveland DW. 52.  2010. Centriole duplication: a lesson in self-control. Cell Cycle 9:2731–36 [Google Scholar]
  53. Holland AJ, Taylor SS. 53.  2006. Cyclin-B1-mediated inhibition of excess separase is required for timely chromosome disjunction. J. Cell Sci. 119:3325–36 [Google Scholar]
  54. Holloway SL, Glotzer M, King RW, Murray AW. 54.  1993. Anaphase is initiated by proteolysis rather than by the inactivation of maturation-promoting factor. Cell 73:1393–402 [Google Scholar]
  55. Howell BJ, Hoffman DB, Fang G, Murray AW, Salmon ED. 55.  2000. Visualization of Mad2 dynamics at kinetochores, along spindle fibers, and at spindle poles in living cells. J. Cell Biol. 150:1233–50 [Google Scholar]
  56. Howell BJ, Moree B, Farrar EM, Stewart S, Fang G, Salmon ED. 56.  2004. Spindle checkpoint protein dynamics at kinetochores in living cells. Curr. Biol. 14:953–64 [Google Scholar]
  57. Hsu JY, Reimann JD, Sorensen CS, Lukas J, Jackson PK. 57.  2002. E2F-dependent accumulation of hEmi1 regulates S phase entry by inhibiting APC(Cdh1). Nat. Cell Biol. 4:358–66 [Google Scholar]
  58. Izawa D, Pines J. 58.  2012. Mad2 and the APC/C compete for the same site on Cdc20 to ensure proper chromosome segregation. J. Cell Biol. 199:27–37 [Google Scholar]
  59. Izawa D, Pines J. 59.  2015. The mitotic checkpoint complex binds a second CDC20 to inhibit active APC/C. Nature 517:631–34 [Google Scholar]
  60. Jaspersen SL, Charles JF, Morgan DO. 60.  1999. Inhibitory phosphorylation of the APC regulator Hct1 is controlled by the kinase Cdc28 and the phosphatase Cdc14. Curr. Biol. 9:227–36 [Google Scholar]
  61. Jeganathan K, Malureanu L, Baker DJ, Abraham SC, van Deursen JM. 61.  2007. Bub1 mediates cell death in response to chromosome missegregation and acts to suppress spontaneous tumorigenesis. J. Cell Biol. 179:255–67 [Google Scholar]
  62. Jeganathan KB, Baker DJ, van Deursen JM. 62.  2006. Securin associates with APCCdh1 in prometaphase but its destruction is delayed by Rae1 and Nup98 until the metaphase/anaphase transition. Cell Cycle 5:366–70 [Google Scholar]
  63. Jeganathan KB, Malureanu L, van Deursen JM. 63.  2005. The Rae1-Nup98 complex prevents aneuploidy by inhibiting securin degradation. Nature 438:1036–39 [Google Scholar]
  64. Jin L, Williamson A, Banerjee S, Philipp I, Rape M. 64.  2008. Mechanism of ubiquitin-chain formation by the human anaphase-promoting complex. Cell 133:653–65 [Google Scholar]
  65. Kapanidou M, Lee S, Bolanos-Garcia VM. 65.  2015. BubR1 kinase: protection against aneuploidy and premature aging. Trends Mol. Med. 21:364–72 [Google Scholar]
  66. Kelly A, Wickliffe KE, Song L, Fedrigo I, Rape M. 66.  2014. Ubiquitin chain elongation requires E3-dependent tracking of the emerging conjugate. Mol. Cell 56:232–45 [Google Scholar]
  67. Kerscher O, Felberbaum R, Hochstrasser M. 67.  2006. Modification of proteins by ubiquitin and ubiquitin-like proteins. Annu. Rev. Cell Dev. Biol. 22:159–80 [Google Scholar]
  68. Kimata Y, Baxter JE, Fry AM, Yamano H. 68.  2008. A role for the Fizzy/Cdc20 family of proteins in activation of the APC/C distinct from substrate recruitment. Mol. Cell 32:576–83 [Google Scholar]
  69. King RW, Peters JM, Tugendreich S, Rolfe M, Hieter P, Kirschner MW. 69.  1995. A 20S complex containing CDC27 and CDC16 catalyzes the mitosis-specific conjugation of ubiquitin to cyclin B. Cell 81:279–88 [Google Scholar]
  70. Kops GJ, Foltz DR, Cleveland DW. 70.  2004. Lethality to human cancer cells through massive chromosome loss by inhibition of the mitotic checkpoint. PNAS 101:8699–704 [Google Scholar]
  71. Kraft C, Vodermaier HC, Maurer-Stroh S, Eisenhaber F, Peters JM. 71.  2005. The WD40 propeller domain of Cdh1 functions as a destruction box receptor for APC/C substrates. Mol. Cell 18:543–53 [Google Scholar]
  72. Kulukian A, Han JS, Cleveland DW. 72.  2009. Unattached kinetochores catalyze production of an anaphase inhibitor that requires a Mad2 template to prime Cdc20 for BubR1 binding. Dev. Cell 16:105–17 [Google Scholar]
  73. Labit H, Fujimitsu K, Bayin NS, Takaki T, Gannon J, Yamano H. 73.  2012. Dephosphorylation of Cdc20 is required for its C-box-dependent activation of the APC/C. EMBO J. 31:3351–62 [Google Scholar]
  74. Lampson MA, Cheeseman IM. 74.  2011. Sensing centromere tension: Aurora B and the regulation of kinetochore function. Trends Cell Biol. 21:133–40 [Google Scholar]
  75. Lara-Gonzalez P, Scott MI, Diez M, Sen O, Taylor SS. 75.  2011. BubR1 blocks substrate recruitment to the APC/C in a KEN-box-dependent manner. J. Cell Sci. 124:4332–45 [Google Scholar]
  76. Lengauer C, Kinzler KW, Vogelstein B. 76.  1997. Genetic instability in colorectal cancers. Nature 386:623–27 [Google Scholar]
  77. Lentini L, Barra V, Schillaci T, Di Leonardo A. 77.  2012. MAD2 depletion triggers premature cellular senescence in human primary fibroblasts by activating a p53 pathway preventing aneuploid cells propagation. J. Cell. Physiol. 227:3324–32 [Google Scholar]
  78. Li M, Fang X, Baker DJ, Guo L, Gao X. 78.  et al. 2010. The ATM-p53 pathway suppresses aneuploidy-induced tumorigenesis. PNAS 107:14188–93 [Google Scholar]
  79. Li M, Fang X, Wei Z, York JP, Zhang P. 79.  2009. Loss of spindle assembly checkpoint-mediated inhibition of Cdc20 promotes tumorigenesis in mice. J. Cell Biol. 185:983–94 [Google Scholar]
  80. Li Y, Benezra R. 80.  1996. Identification of a human mitotic checkpoint gene: hsMAD2. Science 274:246–48 [Google Scholar]
  81. Listovsky T, Oren YS, Yudkovsky Y, Mahbubani HM, Weiss AM. 81.  et al. 2004. Mammalian Cdh1/Fzr mediates its own degradation. EMBO J. 23:1619–26 [Google Scholar]
  82. Listovsky T, Sale JE. 82.  2013. Sequestration of CDH1 by MAD2L2 prevents premature APC/C activation prior to anaphase onset. J. Cell Biol. 203:87–100 [Google Scholar]
  83. Liu D, Vader G, Vromans MJ, Lampson MA, Lens SM. 83.  2009. Sensing chromosome bi-orientation by spatial separation of aurora B kinase from kinetochore substrates. Science 323:1350–53 [Google Scholar]
  84. Liu ST, Chan GK, Hittle JC, Fujii G, Lees E, Yen TJ. 84.  2003. Human MPS1 kinase is required for mitotic arrest induced by the loss of CENP-E from kinetochores. Mol. Biol. Cell 14:1638–51 [Google Scholar]
  85. Luo X, Tang Z, Rizo J, Yu H. 85.  2002. The Mad2 spindle checkpoint protein undergoes similar major conformational changes upon binding to either Mad1 or Cdc20. Mol. Cell 9:59–71 [Google Scholar]
  86. Luo X, Tang Z, Xia G, Wassmann K, Matsumoto T. 86.  et al. 2004. The Mad2 spindle checkpoint protein has two distinct natively folded states. Nat. Struct. Mol. Biol. 11:338–45 [Google Scholar]
  87. Machida YJ, Dutta A. 87.  2007. The APC/C inhibitor, Emi1, is essential for prevention of rereplication. Genes Dev. 21:184–94 [Google Scholar]
  88. Maciejowski J, George KA, Terret ME, Zhang C, Shokat KM, Jallepalli PV. 88.  2010. Mps1 directs the assembly of Cdc20 inhibitory complexes during interphase and mitosis to control M phase timing and spindle checkpoint signaling. J. Cell Biol. 190:89–100 [Google Scholar]
  89. Malureanu LA, Jeganathan KB, Hamada M, Wasilewski L, Davenport J, van Deursen JM. 89.  2009. BubR1 N terminus acts as a soluble inhibitor of cyclin B degradation by APC/C(Cdc20) in interphase. Dev. Cell 16:118–31 [Google Scholar]
  90. Margottin-Goguet F, Hsu JY, Loktev A, Hsieh HM, Reimann JD, Jackson PK. 90.  2003. Prophase destruction of Emi1 by the SCF(βTrCP/Slimb) ubiquitin ligase activates the anaphase promoting complex to allow progression beyond prometaphase. Dev. Cell 4:813–26 [Google Scholar]
  91. Matsumoto ML, Wickliffe KE, Dong KC, Yu C, Bosanac I. 91.  et al. 2010. K11-linked polyubiquitination in cell cycle control revealed by a K11 linkage-specific antibody. Mol. Cell 39:477–84 [Google Scholar]
  92. Meraldi P, Draviam VM, Sorger PK. 92.  2004. Timing and checkpoints in the regulation of mitotic progression. Dev. Cell 7:45–60 [Google Scholar]
  93. Meyer HJ, Rape M. 93.  2014. Enhanced protein degradation by branched ubiquitin chains. Cell 157:910–21 [Google Scholar]
  94. Miller JJ, Summers MK, Hansen DV, Nachury MV, Lehman NL. 94.  et al. 2006. Emi1 stably binds and inhibits the anaphase-promoting complex/cyclosome as a pseudosubstrate inhibitor. Genes Dev. 20:2410–20 [Google Scholar]
  95. Murray AW, Solomon MJ, Kirschner MW. 95.  1989. The role of cyclin synthesis and degradation in the control of maturation promoting factor activity. Nature 339:280–86 [Google Scholar]
  96. Musacchio A, Salmon ED. 96.  2007. The spindle-assembly checkpoint in space and time. Nat. Rev. Mol. Cell Biol. 8:379–93 [Google Scholar]
  97. Nakayama KI, Nakayama K. 97.  2006. Ubiquitin ligases: cell-cycle control and cancer. Nat. Rev. Cancer 6:369–81 [Google Scholar]
  98. Nam HJ, Naylor RM, van Deursen JM. 98.  2015. Centrosome dynamics as a source of chromosomal instability. Trends Cell Biol. 25:65–73 [Google Scholar]
  99. Nam HJ, van Deursen JM. 99.  2014. Cyclin B2 and p53 control proper timing of centrosome separation. Nat. Cell Biol. 16:538–49 [Google Scholar]
  100. Naylor RM, Jeganathan KB, Cao X, van Deursen JM. 100.  2016. Nuclear pore protein NUP88 activates anaphase-promoting complex to promote aneuploidy. J. Clin. Investig. 126:543–59 [Google Scholar]
  101. Orr B, Compton DA. 101.  2013. A double-edged sword: how oncogenes and tumor suppressor genes can contribute to chromosomal instability. Front. Oncol. 3:164 [Google Scholar]
  102. Park I, Lee HO, Choi E, Lee YK, Kwon MS. 102.  et al. 2013. Loss of BubR1 acetylation causes defects in spindle assembly checkpoint signaling and promotes tumor formation. J. Cell Biol. 202:295–309 [Google Scholar]
  103. Pfau SJ, Amon A. 103.  2012. Chromosomal instability and aneuploidy in cancer: from yeast to man. EMBO Rep. 13:515–27 [Google Scholar]
  104. Prinz S, Hwang ES, Visintin R, Amon A. 104.  1998. The regulation of Cdc20 proteolysis reveals a role for APC components Cdc23 and Cdc27 during S phase and early mitosis. Curr. Biol. 8:750–60 [Google Scholar]
  105. Rahmani Z, Gagou ME, Lefebvre C, Emre D, Karess RE. 105.  2009. Separating the spindle, checkpoint, and timer functions of BubR1. J. Cell Biol. 187:597–605 [Google Scholar]
  106. Rape M, Kirschner MW. 106.  2004. Autonomous regulation of the anaphase-promoting complex couples mitosis to S-phase entry. Nature 432:588–95 [Google Scholar]
  107. Reddy SK, Rape M, Margansky WA, Kirschner MW. 107.  2007. Ubiquitination by the anaphase-promoting complex drives spindle checkpoint inactivation. Nature 446:921–25 [Google Scholar]
  108. Reimann JD, Gardner BE, Margottin-Goguet F, Jackson PK. 108.  2001. Emi1 regulates the anaphase-promoting complex by a different mechanism than Mad2 proteins. Genes Dev. 15:3278–85 [Google Scholar]
  109. Ricke RM, van Deursen JM. 109.  2013. Aneuploidy in health, disease, and aging. J. Cell Biol. 201:11–21 [Google Scholar]
  110. Ricke RM, van Ree JH, van Deursen JM. 110.  2008. Whole chromosome instability and cancer: a complex relationship. Trends Genet. 24:457–66 [Google Scholar]
  111. Rodriguez-Bravo V, Maciejowski J, Corona J, Buch HK, Collin P. 111.  et al. 2014. Nuclear pores protect genome integrity by assembling a premitotic and Mad1-dependent anaphase inhibitor. Cell 156:1017–31 [Google Scholar]
  112. Santaguida S, Amon A. 112.  2015. Short- and long-term effects of chromosome mis-segregation and aneuploidy. Nat. Rev. Mol. Cell Biol. 16:473–85 [Google Scholar]
  113. Shah JV, Botvinick E, Bonday Z, Furnari F, Berns M, Cleveland DW. 113.  2004. Dynamics of centromere and kinetochore proteins: implications for checkpoint signaling and silencing. Curr. Biol. 14:942–52 [Google Scholar]
  114. Shindo N, Kumada K, Hirota T. 114.  2012. Separase sensor reveals dual roles for separase coordinating cohesin cleavage and Cdk1 inhibition. Dev. Cell 23:112–23 [Google Scholar]
  115. Silk AD, Zasadil LM, Holland AJ, Vitre B, Cleveland DW, Weaver BA. 115.  2013. Chromosome missegregation rate predicts whether aneuploidy will promote or suppress tumors. PNAS 110:E4134–41 [Google Scholar]
  116. Silkworth WT, Cimini D. 116.  2012. Transient defects of mitotic spindle geometry and chromosome segregation errors. Cell Div. 7:19 [Google Scholar]
  117. Silkworth WT, Nardi IK, Paul R, Mogilner A, Cimini D. 117.  2012. Timing of centrosome separation is important for accurate chromosome segregation. Mol. Biol. Cell 23:401–11 [Google Scholar]
  118. Sivakumar S, Gorbsky GJ. 118.  2015. Spatiotemporal regulation of the anaphase-promoting complex in mitosis. Nat. Rev. Mol. Cell Biol. 16:82–94 [Google Scholar]
  119. Skoufias DA, Andreassen PR, Lacroix FB, Wilson L, Margolis RL. 119.  2001. Mammalian mad2 and bub1/bubR1 recognize distinct spindle-attachment and kinetochore-tension checkpoints. PNAS 98:4492–97 [Google Scholar]
  120. Stegmeier F, Rape M, Draviam VM, Nalepa G, Sowa ME. 120.  et al. 2007. Anaphase initiation is regulated by antagonistic ubiquitination and deubiquitination activities. Nature 446:876–81 [Google Scholar]
  121. Sudakin V, Chan GK, Yen TJ. 121.  2001. Checkpoint inhibition of the APC/C in HeLa cells is mediated by a complex of BUBR1, BUB3, CDC20, and MAD2. J. Cell Biol. 154:925–36 [Google Scholar]
  122. Tanaka TU, Rachidi N, Janke C, Pereira G, Galova M. 122.  et al. 2002. Evidence that the Ipl1-Sli15 (Aurora kinase-INCENP) complex promotes chromosome bi-orientation by altering kinetochore-spindle pole connections. Cell 108:317–29 [Google Scholar]
  123. Taylor SS, Ha E, McKeon F. 123.  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 [Google Scholar]
  124. Taylor SS, McKeon F. 124.  1997. Kinetochore localization of murine Bub1 is required for normal mitotic timing and checkpoint response to spindle damage. Cell 89:727–35 [Google Scholar]
  125. Thompson SL, Compton DA. 125.  2008. Examining the link between chromosomal instability and aneuploidy in human cells. J. Cell Biol. 180:665–72 [Google Scholar]
  126. Thompson SL, Compton DA. 126.  2010. Proliferation of aneuploid human cells is limited by a p53-dependent mechanism. J. Cell Biol. 188:369–81 [Google Scholar]
  127. Thompson SL, Compton DA. 127.  2011. Chromosome missegregation in human cells arises through specific types of kinetochore-microtubule attachment errors. PNAS 108:17974–78 [Google Scholar]
  128. Uhlmann F, Lottspeich F, Nasmyth K. 128.  1999. Sister-chromatid separation at anaphase onset is promoted by cleavage of the cohesin subunit Scc1. Nature 400:37–42 [Google Scholar]
  129. Visintin R, Craig K, Hwang ES, Prinz S, Tyers M, Amon A. 129.  1998. The phosphatase Cdc14 triggers mitotic exit by reversal of Cdk-dependent phosphorylation. Mol. Cell 2:709–18 [Google Scholar]
  130. Vitale I, Galluzzi L, Castedo M, Kroemer G. 130.  2011. Mitotic catastrophe: a mechanism for avoiding genomic instability. Nat. Rev. Mol. Cell Biol. 12:385–92 [Google Scholar]
  131. Vitre BD, Cleveland DW. 131.  2012. Centrosomes, chromosome instability (CIN) and aneuploidy. Curr. Opin. Cell Biol. 24:809–15 [Google Scholar]
  132. Waizenegger I, Gimenez-Abian JF, Wernic D, Peters JM. 132.  2002. Regulation of human separase by securin binding and autocleavage. Curr. Biol. 12:1368–78 [Google Scholar]
  133. Waizenegger IC, Hauf S, Meinke A, Peters JM. 133.  2000. Two distinct pathways remove mammalian cohesin from chromosome arms in prophase and from centromeres in anaphase. Cell 103:399–410 [Google Scholar]
  134. Walczak CE, Cai S, Khodjakov A. 134.  2010. Mechanisms of chromosome behaviour during mitosis. Nat. Rev. Mol. Cell Biol. 11:91–102 [Google Scholar]
  135. Wang W, Kirschner MW. 135.  2013. Emi1 preferentially inhibits ubiquitin chain elongation by the anaphase-promoting complex. Nat. Cell Biol. 15:797–806 [Google Scholar]
  136. Wang Y, Waters J, Leung ML, Unruh A, Roh W. 136.  et al. 2014. Clonal evolution in breast cancer revealed by single nucleus genome sequencing. Nature 512:155–60 [Google Scholar]
  137. Waters JC, Chen RH, Murray AW, Salmon ED. 137.  1998. Localization of Mad2 to kinetochores depends on microtubule attachment, not tension. J. Cell Biol. 141:1181–91 [Google Scholar]
  138. Weaver BA, Silk AD, Montagna C, Verdier-Pinard P, Cleveland DW. 138.  2007. Aneuploidy acts both oncogenically and as a tumor suppressor. Cancer Cell 11:25–36 [Google Scholar]
  139. Welburn JP, Vleugel M, Liu D, Yates JR 3rd, Lampson MA. 139.  et al. 2010. Aurora B phosphorylates spatially distinct targets to differentially regulate the kinetochore-microtubule interface. Mol. Cell 38:383–92 [Google Scholar]
  140. Williams BR, Prabhu VR, Hunter KE, Glazier CM, Whittaker CA. 140.  et al. 2008. Aneuploidy affects proliferation and spontaneous immortalization in mammalian cells. Science 322:703–9 [Google Scholar]
  141. Williamson A, Banerjee S, Zhu X, Philipp I, Iavarone AT, Rape M. 141.  2011. Regulation of ubiquitin chain initiation to control the timing of substrate degradation. Mol. Cell 42:744–57 [Google Scholar]
  142. Xia G, Luo X, Habu T, Rizo J, Matsumoto T, Yu H. 142.  2004. Conformation-specific binding of p31(comet) antagonizes the function of Mad2 in the spindle checkpoint. EMBO J. 23:3133–43 [Google Scholar]
  143. Yang F, Huang Y, Dai W. 143.  2012. Sumoylated BubR1 plays an important role in chromosome segregation and mitotic timing. Cell Cycle 11:797–806 [Google Scholar]
  144. Yang M, Li B, Tomchick DR, Machius M, Rizo J. 144.  et al. 2007. p31comet blocks Mad2 activation through structural mimicry. Cell 131:744–55 [Google Scholar]
  145. Yang Z, Kenny AE, Brito DA, Rieder CL. 145.  2009. Cells satisfy the mitotic checkpoint in Taxol, and do so faster in concentrations that stabilize syntelic attachments. J. Cell Biol. 186:675–84 [Google Scholar]
  146. Zachariae W, Schwab M, Nasmyth K, Seufert W. 146.  1998. Control of cyclin ubiquitination by CDK-regulated binding of Hct1 to the anaphase promoting complex. Science 282:1721–24 [Google Scholar]
  147. Zeng X, Sigoillot F, Gaur S, Choi S, Pfaff KL. 147.  et al. 2010. Pharmacologic inhibition of the anaphase-promoting complex induces a spindle checkpoint-dependent mitotic arrest in the absence of spindle damage. Cancer Cell 18:382–95 [Google Scholar]
  148. Zhang Y, Foreman O, Wigle DA, Kosari F, Vasmatzis G. 148.  et al. 2012. USP44 regulates centrosome positioning to prevent aneuploidy and suppress tumorigenesis. J. Clin. Investig. 122:4362–74 [Google Scholar]
  149. Zou H, McGarry TJ, Bernal T, Kirschner MW. 149.  1999. Identification of a vertebrate sister-chromatid separation inhibitor involved in transformation and tumorigenesis. Science 285:418–22 [Google Scholar]
/content/journals/10.1146/annurev-genet-120215-035303
Loading
/content/journals/10.1146/annurev-genet-120215-035303
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error