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Short- and long-term effects of chromosome mis-segregation and aneuploidy

An Erratum to this article was published on 12 August 2015

This article has been updated

Key Points

  • Aneuploidy is defined as an abnormal karyotype that is not a multiple of the haploid complement.

  • Chromosome mis-segregation causes DNA damage.

  • Micronuclei form during chromosome mis-segregation. Chromosomes within micronuclei are under-replicated and undergo chromothripsis.

  • Chromosome mis-segregation leads to p53 activation.

  • The complex phenotypes caused by aneuploidy are produced by changes in the dosage of specific genes and a generic aneuploidy-associated stress response.

  • Aneuploidy causes proteotoxic stress and impairs proliferation.

  • Aneuploidy is a hallmark of cancer but the relationship between aneuploidy and cancer is complex. Depending on the context, aneuploidy can promote or antagonize malignant transformation.


Dividing cells that experience chromosome mis-segregation generate aneuploid daughter cells, which contain an incorrect number of chromosomes. Although aneuploidy interferes with the proliferation of untransformed cells, it is also, paradoxically, a hallmark of cancer, a disease defined by increased proliferative potential. These contradictory effects are also observed in mouse models of chromosome instability (CIN). CIN can inhibit and promote tumorigenesis. Recent work has provided insights into the cellular consequences of CIN and aneuploidy. Chromosome mis-segregation per se can alter the genome in many more ways than just causing the gain or loss of chromosomes. The short- and long-term effects of aneuploidy are caused by gene-specific effects and a stereotypic aneuploidy stress response. Importantly, these recent findings provide insights into the role of aneuploidy in tumorigenesis.

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Figure 1: Lagging chromosomes experience DNA damage.
Figure 2: Multiple mechanisms could be responsible for p53 activation following chromosome mis-segregation.
Figure 3: Aneuploidy-associated stresses.
Figure 4: Protein quality control is limiting in aneuploid cells.

Change history

  • 12 August 2015

    In the original article, the microtubule attachments to the central, misaligned chromosome in the left part of figure 1b were incorrectly drawn as monotelic rather than merotelic. The figure has now been corrected in the online version of the article. We apologize for any confusion that this may have caused.


  1. 1

    Täckholm, G. Zytologische Studien über die Gattung Rosa. Acta Hort. Berg. 7, 97–381 (in German) (1922).

    Google Scholar 

  2. 2

    Holland, A. J. & Cleveland, D. W. Boveri revisited: chromosomal instability, aneuploidy and tumorigenesis. Nat. Rev. Mol. Cell Biol. 10, 478–487 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3

    Holland, A. J. & Cleveland, D. W. Losing balance: the origin and impact of aneuploidy in cancer. EMBO Rep. 13, 501–514 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4

    Pfau, S. J. & Amon, A. Chromosomal instability and aneuploidy in cancer: from yeast to man. EMBO Rep. 13, 515–527 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5

    Musacchio, A. & Salmon, E. D. The spindle-assembly checkpoint in space and time. Nat. Rev. Mol. Cell Biol. 8, 379–393 (2007).

    CAS  Article  PubMed  Google Scholar 

  6. 6

    Gordon, D. J., Resio, B. & Pellman, D. Causes and consequences of aneuploidy in cancer. Nat. Rev. Genet. 13, 189–203 (2012).

    CAS  PubMed  Google Scholar 

  7. 7

    Upender, M. B. et al. Chromosome transfer induced aneuploidy results in complex dysregulation of the cellular transcriptome in immortalized and cancer cells. Cancer Res. 64, 6941–6949 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8

    Lyle, R., Gehrig, C., Neergaard-Henrichsen, C., Deutsch, S. & Antonarakis, S. E. Gene expression from the aneuploid chromosome in a trisomy mouse model of Down syndrome. Genome Res. 14, 1268–1274 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9

    Huettel, B., Kreil, D. P., Matzke, M. & Matzke, A. J. M. Effects of aneuploidy on genome structure, expression, and interphase organization in Arabidopsis thaliana. PLoS Genet. 4, e1000226 (2008).

    PubMed  PubMed Central  Google Scholar 

  10. 10

    Stingele, S. et al. Global analysis of genome, transcriptome and proteome reveals the response to aneuploidy in human cells. Mol. Syst. Biol. 8, 1–12 (2012).

    Google Scholar 

  11. 11

    Dephoure, N. et al. Quantitative proteomic analysis reveals posttranslational responses to aneuploidy in yeast. eLife 3, e03023 (2014). This paper reports that changes in gene copy number lead to corresponding changes in protein expression in 80% of budding yeast genes. It also reports the identification of a new gene expression signature that is characterized by the upregulation of proteins involved in the oxidative-stress response.

    PubMed  PubMed Central  Google Scholar 

  12. 12

    Kahlem, P. et al. Transcript level alterations reflect gene dosage effects across multiple tissues in a mouse model of Down syndrome. Genome Res. 14, 1258–1267 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13

    Pavelka, N. et al. Aneuploidy confers quantitative proteome changes and phenotypic variation in budding yeast. Nature 468, 321–325 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14

    Torres, E. M. et al. Effects of aneuploidy on cellular physiology and cell division in haploid yeast. Science 317, 916–924 (2007).

    CAS  PubMed  Google Scholar 

  15. 15

    Vacík, T. et al. Segmental trisomy of chromosome 17: a mouse model of human aneuploidy syndromes. Proc. Natl Acad. Sci. USA 102, 4500–4505 (2005).

    PubMed  Google Scholar 

  16. 16

    Williams, B. R. et al. Aneuploidy affects proliferation and spontaneous immortalization in mammalian cells. Science 322, 703–709 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17

    Hassold, T. & Hunt, P. To err (meiotically) is human: the genesis of human aneuploidy. Nat. Rev. Genet. 2, 280–291 (2001).

    CAS  PubMed  Google Scholar 

  18. 18

    Hanks, S. et al. Constitutional aneuploidy and cancer predisposition caused by biallelic mutations in BUB1B. Nat. Genet. 36, 1159–1161 (2004).

    CAS  PubMed  Google Scholar 

  19. 19

    Sears, D. D., Hegemann, J. H. & Hieter, P. Meiotic recombination and segregation of human-derived artificial chromosomes in Saccharomyces cerevisiae. Proc. Natl Acad. Sci. USA 89, 5296–5300 (1992).

    CAS  PubMed  Google Scholar 

  20. 20

    Hartwell, L. H. & Smith, D. Altered fidelity of mitotic chromosome transmission in cell cycle mutants of S. cerevisiae. Genetics 110, 381–395 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21

    Brown, M. et al. Fidelity of mitotic chromosome transmission. Cold Spring Harb. Symp. Quant. Biol. 56, 359–365 (1991).

    CAS  PubMed  Google Scholar 

  22. 22

    Storchova, Z. et al. Genome-wide genetic analysis of polyploidy in yeast. Nature 443, 541–547 (2006).

    CAS  PubMed  Google Scholar 

  23. 23

    Thompson, S. L. & Compton, D. A. Examining the link between chromosomal instability and aneuploidy in human cells. J. Cell Biol. 180, 665–672 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24

    Cimini, D., Tanzarella, C. & Degrassi, F. Differences in malsegregation rates obtained by scoring ana-telophases or binucleate cells. Mutagenesis 14, 563–568 (1999).

    CAS  PubMed  Google Scholar 

  25. 25

    Rehen, S. K. et al. Constitutional aneuploidy in the normal human brain. J. Neurosci. 25, 2176–2180 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26

    Knouse, K. A., Wu, J., Whittaker, C. A. & Amon, A. Single cell sequencing reveals low levels of aneuploidy across mammalian tissues. Proc. Natl Acad. Sci. 111, 13409–13414 (2014). This analysis shows that aneuploid karyotypes are rare in normal tissues.

    CAS  PubMed  Google Scholar 

  27. 27

    Duncan, A. W. et al. Aneuploidy as a mechanism for stress-induced liver adaptation. J. Clin. Invest. 122, 3307–3315 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28

    Duncan, A. W. et al. Frequent aneuploidy among normal human hepatocytes. Gastroenterology 142, 25–28 (2012).

    PubMed  Google Scholar 

  29. 29

    Duncan, A. W. et al. The ploidy conveyor of mature hepatocytes as a source of genetic variation. Nature 467, 707–710 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30

    Rehen, S. K. et al. Chromosomal variation in neurons of the developing and adult mammalian nervous system. Proc. Natl Acad. Sci. USA 98, 13361–13366 (2001).

    CAS  PubMed  Google Scholar 

  31. 31

    Pack, S. D. et al. Individual adult human neurons display aneuploidy: detection by fluorescence in situ hybridization and single neuron PCR. Cell Cycle 4, 1758–1760 (2005).

    CAS  PubMed  Google Scholar 

  32. 32

    Yurov, Y. B. et al. Aneuploidy and confined chromosomal mosaicism in the developing human brain. PLoS ONE 2, e558 (2007).

    PubMed  PubMed Central  Google Scholar 

  33. 33

    Faggioli, F., Wang, T., Vijg, J. & Montagna, C. Chromosome-specific accumulation of aneuploidy in the aging mouse brain. Hum. Mol. Genet. 21, 5246–5253 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34

    McConnell, M. J. et al. Mosaic copy number variation in human neurons. Science 342, 632–637 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    Cai, X. et al. Single-cell, genome-wide sequencing identifies clonal somatic copy-number variation in the human brain. Cell Rep. 8, 1280–1289 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36

    Hassold, T. et al. Human aneuploidy: incidence, origin, and etiology. Environ. Mol. Mutagen. 28, 167–175 (1996).

    CAS  PubMed  Google Scholar 

  37. 37

    Hartl, D. L. & Jones, E. W. Genetics: Analysis of Genes and Genomes (Jones & Bartlett Learning, 2005).

    Google Scholar 

  38. 38

    Janssen, A., van der Burg, M., Szuhai, K., Kops, G. J. P. L. & Medema, R. H. Chromosome segregation errors as a cause of DNA damage and structural chromosome aberrations. Science 333, 1895–1898 (2011). This paper shows that mis-segregating chromosomes can be damaged during cytokinesis and can be the source of structural chromosome aberrations in aneuploid daughter cells.

    CAS  PubMed  Google Scholar 

  39. 39

    Crasta, K. et al. DNA breaks and chromosome pulverization from errors in mitosis. Nature 482, 53–58 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. 40

    Hoffelder, D. et al. Resolution of anaphase bridges in cancer cells. Chromosoma 112, 389–397 (2004).

    PubMed  Google Scholar 

  41. 41

    Terradas, M., Martín, M., Tusell, L. & Genescà, A. DNA lesions sequestered in micronuclei induce a local defective-damage response. DNA Repair 8, 1225–1234 (2009).

    CAS  PubMed  Google Scholar 

  42. 42

    Terradas, M., Martín, M., Hernández, L., Tusell, L. & Genescà, A. Nuclear envelope defects impede a proper response to micronuclear DNA lesions. Mutat. Res. 729, 35–40 (2012).

    CAS  PubMed  Google Scholar 

  43. 43

    Xu, B. et al. Replication stress induces micronuclei comprising of aggregated DNA double-strand breaks. PLoS ONE 6, e18618 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44

    Newport, J. Nuclear reconstitution in vitro: stages of assembly around protein-free DNA. Cell 48, 205–217 (1987).

    CAS  PubMed  Google Scholar 

  45. 45

    Hatch, E. M. et al. Catastrophic nuclear envelope collapse in cancer cell micronuclei. Cell 154, 47–60 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46

    Zhang, C.-Z. et al. Chromothripsis from DNA damage in micronuclei. Nature 522, 179–184 (2015). Using a combination of live-cell imaging and single-cell genome sequencing, this study provides the first evidence for a causative role of micronucleation in chromothripsis.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47

    Liu, P. et al. Chromosome catastrophes involve replication mechanisms generating complex genomic rearrangements. Cell 146, 889–903 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48

    Stephens, P. J. et al. Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell 144, 27–40 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49

    Forment, J. V., Kaidi, A. & Jackson, S. P. Chromothripsis and cancer: causes and consequences of chromosome shattering. Nat. Rev. Cancer 12, 663–670 (2012).

    CAS  PubMed  Google Scholar 

  50. 50

    Zhang, C. Z., Leibowitz, M. L. & Pellman, D. Chromothripsis and beyond: rapid genome evolution from complex chromosomal rearrangements. Genes Dev. 27, 2513–2530 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51

    Thompson, S. L. & Compton, D. A. Proliferation of aneuploid human cells is limited by a p53-dependent mechanism. J. Cell Biol. 188, 369–381 (2010). This study shows that chromosome mis-segregation leads to p53 activation, which limits the proliferation of aneuploid cells.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52

    Dobles, M., Liberal, V., Scott, M. L., Benezra, R. & Sorger, P. K. Chromosome missegregation and apoptosis in mice lacking the mitotic checkpoint protein Mad2. Cell 101, 635–645 (2000).

    CAS  PubMed  Google Scholar 

  53. 53

    Burds, A. A., Lutum, A. S. & Sorger, P. K. Generating chromosome instability through the simultaneous deletion of Mad2 and p53. Proc. Natl Acad. Sci. USA 102, 11296–11301 (2005).

    CAS  PubMed  Google Scholar 

  54. 54

    Li, M. et al. The ATM–p53 pathway suppresses aneuploidy-induced tumorigenesis. Proc. Natl Acad. Sci. 107, 14188–14193 (2010).

    CAS  PubMed  Google Scholar 

  55. 55

    Uetake, Y. & Sluder, G. Prolonged prometaphase blocks daughter cell proliferation despite normal completion of mitosis. Curr. Biol. 20, 1666–1671 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56

    Orth, J. D., Loewer, A., Lahav, G. & Mitchison, T. J. Prolonged mitotic arrest triggers partial activation of apoptosis, resulting in DNA damage and p53 induction. Mol. Biol. Cell 23, 567–576 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57

    Hayashi, M. T., Cesare, A. J., Fitzpatrick, J. A. J., Lazzerini-Denchi, E. & Karlseder, J. A telomere-dependent DNA damage checkpoint induced by prolonged mitotic arrest. Nat. Struct. Mol. Biol. 19, 387–394 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58

    Blagosklonny, M. V., Demidenko, Z. N. & Fojo, T. Inhibition of transcription results in accumulation of Wt p53 followed by delayed outburst of p53-inducible proteins: p53 as a sensor of transcriptional integrity. Cell Cycle 1, 67–74 (2002).

    CAS  PubMed Central  PubMed  Google Scholar 

  59. 59

    Blagosklonny, M. V. Prolonged mitosis versus tetraploid checkpoint: how p53 measures the duration of mitosis. Cell Cycle 5, 971–975 (2006).

    CAS  PubMed  Google Scholar 

  60. 60

    Demidenko, Z. N. et al. Mechanism of G1-like arrest by low concentrations of paclitaxel: next cell cycle p53-dependent arrest with sub G1 DNA content mediated by prolonged mitosis. Oncogene 27, 4402–4410 (2008).

    CAS  PubMed  Google Scholar 

  61. 61

    Tang, Y.-C., Williams, B. R., Siegel, J. J. & Amon, A. Identification of aneuploidy-selective antiproliferation compounds. Cell 144, 499–512 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62

    Torres, E. M., Williams, B. R. & Amon, A. Aneuploidy: cells losing their balance. Genetics 179, 737–746 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63

    Torres, E. M. et al. Identification of aneuploidy-tolerating mutations. Cell 143, 71–83 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64

    Chikashige, Y. et al. Gene expression and distribution of Swi6 in partial aneuploids of the fission yeast Schizosaccharomyces pombe. Cell Struct. Funct. 32, 149–161 (2007).

    CAS  PubMed  Google Scholar 

  65. 65

    Mao, R., Zielke, C. L., Ronald Zielke, H. & Pevsner, J. Global up-regulation of chromosome 21 gene expression in the developing Down syndrome brain. Genomics 81, 457–467 (2003).

    CAS  PubMed  Google Scholar 

  66. 66

    Kurnit, D. M. Down syndrome: gene dosage at the transcriptional level in skin fibroblasts. Proc. Natl Acad. Sci. USA 76, 2372–2375 (1979).

    CAS  PubMed  Google Scholar 

  67. 67

    Guo, M. & Birchler, J. A. Trans-acting dosage effects on the expression of model gene systems in maize aneuploids. Science 266, 1999–2002 (1994).

    CAS  PubMed  Google Scholar 

  68. 68

    Kim, J. C. et al. Integrative analysis of gene amplification in Drosophila follicle cells: parameters of origin activation and repression. Genes Dev. 25, 1384–1398 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69

    Stenberg, P. & Larsson, J. Buffering and the evolution of chromosome-wide gene regulation. Chromosoma 120, 213–225 (2011).

    PubMed  PubMed Central  Google Scholar 

  70. 70

    Larsson, J., Chen, J. D., Rasheva, V., Rasmuson-Lestander, A. & Pirrotta, V. Painting of fourth, a chromosome-specific protein in Drosophila. Proc. Natl Acad. Sci. USA 98, 6273–6278 (2001).

    CAS  PubMed  Google Scholar 

  71. 71

    Miclaus, M., Xu, J.-H. & Messing, J. Differential gene expression and epiregulation of alpha zein gene copies in maize haplotypes. PLoS Genet. 7, e1002131 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72

    Futcher, B. & Carbon, J. Toxic effects of excess cloned centromeres. Mol. Cell. Biol. 6, 2213–2222 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73

    Oromendia, A. B., Dodgson, S. E. & Amon, A. Aneuploidy causes proteotoxic stress in yeast. Genes Dev. 26, 2696–2708 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74

    Girirajan, S., Campbell, C. D. & Eichler, E. E. Human copy number variation and complex genetic disease. Annu. Rev. Genet. 45, 203–226 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 75

    Tang, Y.-C. & Amon, A. Gene copy-number alterations: a cost-benefit analysis. Cell 152, 394–405 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76

    Isacson, O., Seo, H., Lin, L., Albeck, D. & Granholm, A. C. Alzheimer's disease and Down's syndrome: roles of APP, trophic factors and ACh. Trends Neurosci. 25, 79–84 (2002).

    CAS  PubMed  Google Scholar 

  77. 77

    Hanemann, C. O. & Müller, H. W. Pathogenesis of Charcot–Marie–Tooth 1A (CMT1A) neuropathy. Trends Neurosci. 21, 282–286 (1998).

    CAS  PubMed  Google Scholar 

  78. 78

    Katz, W., Weinstein, B. & Solomon, F. Regulation of tubulin levels and microtubule assembly in Saccharomyces cerevisiae: consequences of altered tubulin gene copy number. Mol. Cell. Biol. 10, 5286–5294 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79

    Moriya, H., Makanae, K., Watanabe, K., Chino, A. & Shimizu-Yoshida, Y. Robustness analysis of cellular systems using the genetic tug-of-war method. Mol. Biosyst. 8, 2513–2522 (2012).

    CAS  PubMed  Google Scholar 

  80. 80

    Deutschbauer, A. M. et al. Mechanisms of haploinsufficiency revealed by genome-wide profiling in yeast. Genetics 169, 1915–1925 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. 81

    Kim, D.-U. et al. Analysis of a genome-wide set of gene deletions in the fission yeast Schizosaccharomyces pombe. Nat. Biotechnol. 28, 617–623 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82

    Das, I. et al. Hedgehog agonist therapy corrects structural and cognitive deficits in a Down syndrome mouse model. Sci. Transl. Med. 5, 201ra120 (2013).

    PubMed  PubMed Central  Google Scholar 

  83. 83

    Jiang, J. et al. Translating dosage compensation to trisomy 21. Nature 500, 296–300 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84

    Bonney, M. E., Moriya, H. & Amon, A. Aneuploid proliferation defects in yeast are not driven by copy number changes of a few dosage sensitive genes. Genes Dev. 29, 898–903 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 85

    Sheltzer, J. M., Torres, E. M., Dunham, M. J. & Amon, A. Transcriptional consequences of aneuploidy. Proc. Natl Acad. Sci. 109, 12644–12649 (2012).

    CAS  PubMed  Google Scholar 

  86. 86

    Foijer, F. et al. Chromosome instability induced by Mps1 and p53 mutation generates aggressive lymphomas exhibiting aneuploidy-induced stress. Proc. Natl Acad. Sci. 111, 13427–13432 (2014).

    CAS  PubMed  Google Scholar 

  87. 87

    Dürrbaum, M. et al. Unique features of the transcriptional response to model aneuploidy in human cells. BMC Genomics 15, 139 (2014).

    PubMed  PubMed Central  Google Scholar 

  88. 88

    Gasch, A. P. Comparative genomics of the environmental stress response in ascomycete fungi. Yeast 24, 961–976 (2007).

    CAS  PubMed  Google Scholar 

  89. 89

    Gasch, A. P. et al. Genomic expression programs in the response of yeast cells to environmental changes. Mol. Biol. Cell 11, 4241–4257 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90

    Carter, S. L., Eklund, A. C., Kohane, I. S., Harris, L. N. & Szallasi, Z. A signature of chromosomal instability inferred from gene expression profiles predicts clinical outcome in multiple human cancers. Nat. Genet. 38, 1043–1048 (2006).

    CAS  PubMed  Google Scholar 

  91. 91

    Venet, D., Dumont, J. E. & Detours, V. Most random gene expression signatures are significantly associated with breast cancer outcome. PLoS Comput. Biol. 7, e1002240 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92

    Sheltzer, J. M. A transcriptional and metabolic signature of primary aneuploidy is present in chromosomally unstable cancer cells and informs clinical prognosis. Cancer Res. 73, 6401–6412 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93

    Simpson, M. V. The release of labeled amino acids from the proteins of rat liver slices. J. Biol. Chem. 201, 143–154 (1953).

    CAS  PubMed  Google Scholar 

  94. 94

    Balch, W. E., Morimoto, R. I., Dillin, A. & Kelly, J. W. Adapting proteostasis for disease intervention. Science 319, 916–919 (2008).

    CAS  PubMed  Google Scholar 

  95. 95

    Tyedmers, J., Mogk, A. & Bukau, B. Cellular strategies for controlling protein aggregation. Nat. Rev. Mol. Cell Biol. 11, 777–788 (2010).

    CAS  PubMed  Google Scholar 

  96. 96

    Dobson, C. M. Protein folding and misfolding. Nature 426, 884–890 (2003).

    CAS  PubMed  Google Scholar 

  97. 97

    Jahn, T. R. & Radford, S. E. The Yin and Yang of protein folding. FEBS J. 272, 5962–5970 (2005).

    CAS  PubMed  Google Scholar 

  98. 98

    Kirkin, V., McEwan, D. G., Novak, I. & Dikic, I. A role for ubiquitin in selective autophagy. Mol. Cell 34, 259–269 (2009).

    CAS  PubMed  Google Scholar 

  99. 99

    Ding, W.-X. & Yin, X.-M. Sorting, recognition and activation of the misfolded protein degradation pathways through macroautophagy and the proteasome. Autophagy 4, 141–150 (2008).

    CAS  PubMed  Google Scholar 

  100. 100

    Taipale, M., Jarosz, D. F. & Lindquist, S. HSP90 at the hub of protein homeostasis: emerging mechanistic insights. Nat. Rev. Mol. Cell Biol. 11, 515–528 (2010).

    CAS  PubMed  Google Scholar 

  101. 101

    Donnelly, N., Passerini, V., Dürrbaum, M., Stingele, S. & Storchova, Z. HSF1 deficiency and impaired HSP90-dependent protein folding are hallmarks of aneuploid human cells. EMBO J. 33, 2374–2387 (2014). This study shows that HSP90-mediated protein folding is reduced in aneuploid mammalian cells, providing a link between aneuploidy and proteotoxic stress.

    CAS  PubMed  PubMed Central  Google Scholar 

  102. 102

    Boulon, S. et al. HSP90 and its R2TP/prefoldin-like cochaperone are involved in the cytoplasmic assembly of RNA polymerase II. Mol. Cell 39, 912–924 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. 103

    Li, G.-W., Burkhardt, D., Gross, C. & Weissman, J. S. Quantifying absolute protein synthesis rates reveals principles underlying allocation of cellular resources. Cell 157, 624–635 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. 104

    Niwa, O., Tange, Y. & Kurabayashi, A. Growth arrest and chromosome instability in aneuploid yeast. Yeast 23, 937–950 (2006).

    CAS  PubMed  Google Scholar 

  105. 105

    Segal, D. J. & McCoy, E. E. Studies on Down's syndrome in tissue culture. I. Growth rates and protein contents of fibroblast cultures. J. Cell. Physiol. 83, 85–90 (1974).

    CAS  PubMed  Google Scholar 

  106. 106

    Thorburn, R. R. et al. Aneuploid yeast strains exhibit defects in cell growth and passage through START. Mol. Biol. Cell 24, 1274–1289 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. 107

    Baker, D. J. et al. BubR1 insufficiency causes early onset of aging-associated phenotypes and infertility in mice. Nat. Genet. 36, 744–749 (2004).

    CAS  PubMed  Google Scholar 

  108. 108

    Weaver, B. A. A., Silk, A. D., Montagna, C., Verdier-Pinard, P. & Cleveland, D. W. Aneuploidy acts both oncogenically and as a tumor suppressor. Cancer Cell 11, 25–36 (2007).

    CAS  PubMed  Google Scholar 

  109. 109

    Babu, J. R. et al. Rae1 is an essential mitotic checkpoint regulator that cooperates with Bub3 to prevent chromosome missegregation. J. Cell Biol. 160, 341–353 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. 110

    Makanae, K., Kintaka, R., Makino, T., Kitano, H. & Moriya, H. Identification of dosage-sensitive genes in Saccharomyces cerevisiae using the genetic tug-of-war method. Genome Res. 23, 300–311 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. 111

    Mitelman, F., Johansson, B. & Mertens, F. Mitelman database of chromosome aberrations and gene fusions in cancer. [online], (2014).

  112. 112

    Beroukhim, R. et al. The landscape of somatic copy-number alteration across human cancers. Nature 463, 899–905 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 113

    Cahill, D. P. et al. Characterization of MAD2B and other mitotic spindle checkpoint genes. Genomics 58, 181–187 (1999).

    CAS  PubMed  Google Scholar 

  114. 114

    Haruki, N. et al. Molecular analysis of the mitotic checkpoint genes BUB1, BUBR1 and BUB3 in human lung cancers. Cancer Lett. 162, 201–205 (2001).

    CAS  PubMed  Google Scholar 

  115. 115

    Gemma, A. et al. Somatic mutation of the hBUB1 mitotic checkpoint gene in primary lung cancer. Genes Chromosomes Cancer 29, 213–218 (2000).

    CAS  PubMed  Google Scholar 

  116. 116

    Manning, A. L., Longworth, M. S. & Dyson, N. J. Loss of pRB causes centromere dysfunction and chromosomal instability. Genes Dev. 24, 1364–1376 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. 117

    Manning, A. L. & Dyson, N. J. pRB, a tumor suppressor with a stabilizing presence. Trends Cell Biol. 21, 433–441 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 118

    Tighe, A. Truncating APC mutations have dominant effects on proliferation, spindle checkpoint control, survival and chromosome stability. J. Cell Sci. 117, 6339–6353 (2004).

    CAS  PubMed  Google Scholar 

  119. 119

    Davoli, T. et al. Cumulative haploinsufficiency and triplosensitivity drive aneuploidy patterns and shape the cancer genome. Cell 155, 948–962 (2013). By analysing genome sequence data from cancerous and normal tissues, this study provides evidence that aneuploidy drives tumorigenesis through losses of tumour-suppressor genes and gains of oncogenes.

    CAS  PubMed  PubMed Central  Google Scholar 

  120. 120

    Sussan, T. E., Yang, A., Li, F., Ostrowski, M. C. & Reeves, R. H. Trisomy represses ApcMin-mediated tumours in mouse models of Down's syndrome. Nature 451, 73–75 (2008).

    CAS  PubMed  Google Scholar 

  121. 121

    Hasle, H. et al. Risks of leukaemia and solid tumours in individuals with Down's syndrome. Lancet 355, 165–169 (2001).

    Google Scholar 

  122. 122

    Baek, K.-H. et al. Down's syndrome suppression of tumour growth and the role of the calcineurin inhibitor DSCR1. Nature 459, 1126–1130 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. 123

    Paulsson, K. & Johansson, B. Trisomy 8 as the sole chromosomal aberration in acute myeloid leukemia and myelodysplastic syndromes. Pathol. Biol. 55, 37–48 (2007).

    CAS  PubMed  Google Scholar 

  124. 124

    Jones, L. et al. Gain of MYC underlies recurrent trisomy of the MYC chromosome in acute promyelocytic leukemia. J. Exp. Med. 207, 2581–2594 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. 125

    Greenberg, R. A. et al. Short dysfunctional telomeres impair tumorigenesis in the INK4aΔ2/3 cancer-prone mouse. Cell 97, 515–525 (1999).

    CAS  PubMed  Google Scholar 

  126. 126

    Chin, L. et al. p53 deficiency rescues the adverse effects of telomere loss and cooperates with telomere dysfunction to accelerate carcinogenesis. Cell 97, 527–538 (1999).

    CAS  PubMed  Google Scholar 

  127. 127

    Sotillo, R., Schvartzman, J.-M., Socci, N. D. & Benezra, R. Mad2-induced chromosome instability leads to lung tumour relapse after oncogene withdrawal. Nature 464, 436–440 (2010). This study shows that tumour relapse after oncogene withdrawal is accelerated under conditions of increased chromosome mis-segregation in a KRAS -driven model of lung cancer. This finding indicates that aneuploidy can facilitate the emergence of resistant karyotypes that confer an evolutionary advantage to the tumour.

    CAS  PubMed  PubMed Central  Google Scholar 

  128. 128

    Silk, A. D. et al. Chromosome missegregation rate predicts whether aneuploidy will promote or suppress tumors. Proc. Natl Acad. Sci. 110, E4134–E4141 (2013). This article suggests that, although low levels of chromosome mis-segregation can accelerate the generation of karyotypes that promote tumorigenesis, high rates of chromosome gain and loss lead to tumour suppression and cell death.

    CAS  PubMed  Google Scholar 

  129. 129

    Zhu, J., Pavelka, N., Bradford, W. D., Rancati, G. & Li, R. Karyotypic determinants of chromosome instability in aneuploid budding yeast. PLoS Genet. 8, e1002719 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. 130

    Sheltzer, J. M. et al. Aneuploidy drives genomic instability in yeast. Science 333, 1026–1030 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. 131

    Rancati, G. et al. Aneuploidy underlies rapid adaptive evolution of yeast cells deprived of a conserved cytokinesis motor. Cell 135, 879–893 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. 132

    Selmecki, A., Forche, A. & Berman, J. Aneuploidy and isochromosome formation in drug-resistant Candida albicans. Science 313, 367–370 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. 133

    Yona, A. H. et al. Chromosomal duplication is a transient evolutionary solution to stress. Proc. Natl Acad. Sci. 109, 21010–21015 (2012).

    CAS  PubMed  Google Scholar 

  134. 134

    Chen, G. et al. Targeting the adaptability of heterogeneous aneuploids. Cell 160, 771–784 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. 135

    London, N. & Biggins, S. Signalling dynamics in the spindle checkpoint response. Nat. Rev. Mol. Cell Biol. 15, 736–747 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. 136

    Cimini, D. et al. Merotelic kinetochore orientation is a major mechanism of aneuploidy in mitotic mammalian tissue cells. J. Cell Biol. 153, 517–527 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. 137

    Niwa, O., Matsumoto, T. & Yanagida, M. Construction of a mini-chromosome by deletion and its mitotic and meiotic behaviour in fission yeast. Mol. Gen. Genet. 203, 397–405 (1986).

    CAS  Google Scholar 

  138. 138

    Weaver, B. A. A. & Cleveland, D. W. Does aneuploidy cause cancer? Curr. Opin. Cell Biol. 18, 658–667 (2006).

    CAS  PubMed  Google Scholar 

  139. 139

    Niwa, O., Matsumoto, T., Chikashige, Y. & Yanagida, M. Characterization of Schizosaccharomyces pombe minichromosome deletion derivatives and a functional allocation of their centromere. EMBO J. 8, 3045–3052 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. 140

    Zeng, Y., Li, H., Schweppe, N. M., Hawley, R. S. & Gilliland, W. D. Statistical analysis of nondisjunction assays in Drosophila. Genetics 186, 505–513 (2010).

    PubMed  PubMed Central  Google Scholar 

  141. 141

    Gregg, T. G. & Day, J. W. Nondisjunction of the X chromosomes in females of Drosophila hydei. Genetica 36, 172–182 (1965).

    PubMed  Google Scholar 

  142. 142

    Koehler, K. E., Hawley, R. S., Sherman, S. & Hassold, T. Recombination and nondisjunction in humans and flies. Hum. Mol. Genet. 5, 1495–1504 (1996).

    CAS  PubMed  Google Scholar 

  143. 143

    Bond, D. J. & Chandley, A. C. Aneuploidy (Oxford Monographs on Medical Genetics) (Oxford University Press, 1983).

    Google Scholar 

  144. 144

    Martin, R. H., Ko, E. & Rademaker, A. Distribution of aneuploidy in human gametes: comparison between human sperm and oocytes. Am. J. Med. Genet. 39, 321–331 (1991).

    CAS  PubMed  Google Scholar 

  145. 145

    Martin, R. H. & Rademaker, A. The frequency of aneuploidy among individual chromosomes in 6,821 human sperm chromosome complements. Cytogenet. Cell Genet. 53, 103–107 (1990).

    CAS  PubMed  Google Scholar 

  146. 146

    Templado, C., Vidal, F. & Estop, A. Aneuploidy in human spermatozoa. Cytogenet. Genome Res. 133, 91–99 (2011).

    CAS  PubMed  Google Scholar 

  147. 147

    Pellestor, F., Andréo, B., Anahory, T. & Hamamah, S. The occurrence of aneuploidy in human: lessons from the cytogenetic studies of human oocytes. Eur. J. Med. Genet. 49, 103–116 (2006).

    PubMed  Google Scholar 

  148. 148

    Pacchierotti, F., Adler, I.-D., Eichenlaub-Ritter, U. & Mailhes, J. B. Gender effects on the incidence of aneuploidy in mammalian germ cells. Environ. Res. 104, 46–69 (2007).

    CAS  PubMed  Google Scholar 

  149. 149

    Obradors, A. et al. Whole-chromosome aneuploidy analysis in human oocytes: focus on comparative genomic hybridization. Cytogenet. Genome Res. 133, 119–126 (2011).

    CAS  PubMed  Google Scholar 

  150. 150

    Nagaoka, S. I., Hassold, T. J. & Hunt, P. A. Human aneuploidy: mechanisms and new insights into an age-old problem. Nat. Rev. Genet. 13, 493–504 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

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The authors apologize to our colleagues whose work we were not able to cite owing to space limitations. Work in the Amon laboratory is supported by grants from the US National Institutes of Health (GM56800), the Howard Hughes Medical Institute and the Kathy and Curt Marble Cancer Research Fund. S.S. was supported by the American Italian Cancer Foundation and by a Fellowship in Cancer Research from Marie Curie Actions and the Italian Association for Cancer Research.

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Correspondence to Angelika Amon.

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Spectral karyotyping

(SKY). A cytogenetic technique used to simultaneously visualize all chromosomes in a cell by using different fluorescently labelled probes for each chromosome.


A process in which entire chromosomes become fragmented and then are repaired in a seemingly random manner, leading to dozens (sometimes even hundreds) of rearrangements within a single chromosome.

Dosage compensation

Alteration of mRNA or protein expression to compensate for variation in DNA copy number.

Chromosomal instability

(CIN). A condition in which the rate of chromosome mis-segregation is elevated.

Proteotoxic stress

A cellular stress elicited by unfolded and/or misfolded proteins.

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Santaguida, S., Amon, A. Short- and long-term effects of chromosome mis-segregation and aneuploidy. Nat Rev Mol Cell Biol 16, 473–485 (2015).

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