Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

The diverse consequences of aneuploidy

Abstract

Aneuploidy, or imbalanced chromosome number, has profound effects on eukaryotic cells. In humans, aneuploidy is associated with various pathologies, including cancer, which suggests that it mediates a proliferative advantage under these conditions. Here, we discuss physiological changes triggered by aneuploidy, such as altered cell growth, transcriptional changes, proteotoxic stress, genomic instability and response to interferons, and how cancer cells adapt to the changing aneuploid genome.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Routes to whole-chromosome aneuploidy.
Fig. 2: Models of aneuploidy.
Fig. 3: Global and chromosome-specific changes in gene expression in response to aneuploidy.
Fig. 4: Cellular responses and adaptations to whole-chromosome aneuploidy.

Similar content being viewed by others

References

  1. Peter, J. et al. Genome evolution across 1,011 Saccharomyces cerevisiae isolates. Nature 556, 339–344 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Duan, S. F. et al. The origin and adaptive evolution of domesticated populations of yeast from Far East Asia. Nat. Commun. 9, 2690 (2018).

    PubMed  PubMed Central  Google Scholar 

  3. Pilo, D., Carvalho, S., Pereira, P., Gaspar, M. B. & Leitao, A. Is metal contamination responsible for increasing aneuploidy levels in the Manila clam Ruditapes philippinarum? Sci. Total Environ. 577, 340–348 (2017).

    CAS  PubMed  Google Scholar 

  4. Tumova, P., Uzlikova, M., Jurczyk, T. & Nohynkova, E. Constitutive aneuploidy and genomic instability in the single-celled eukaryote Giardia intestinalis. Microbiologyopen 5, 560–574 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Leitao, A., Boudry, P. & Thiriot-Quievreux, C. Evidence of differential chromosome loss in aneuploid karyotypes of the Pacific oyster. Crassostrea gigas. Genome 44, 735–737 (2001).

    CAS  PubMed  Google Scholar 

  6. 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 

  7. Lee, A. J. et al. Chromosomal instability confers intrinsic multidrug resistance. Cancer Res. 71, 1858–1870 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Swanton, C. et al. Chromosomal instability determines taxane response. Proc. Natl Acad. Sci. USA 106, 8671–8676 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Kuznetsova, A. Y. et al. Chromosomal instability, tolerance of mitotic errors and multidrug resistance are promoted by tetraploidization in human cells. Cell Cycle 14, 2810–2820 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Turajlic, S. & Swanton, C. Metastasis as an evolutionary process. Science 352, 169–175 (2016).

    CAS  PubMed  Google Scholar 

  11. Bakhoum, S. F. et al. Chromosomal instability drives metastasis through a cytosolic DNA response. Nature 553, 467–472 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Heng, H. H. et al. Stochastic cancer progression driven by non-clonal chromosome aberrations. J. Cell Physiol. 208, 461–472 (2006).

    CAS  PubMed  Google Scholar 

  13. McClelland, S. E. Role of chromosomal instability in cancer progression. Endocr. Relat. Cancer 24, T23–T31 (2017).

    CAS  PubMed  Google Scholar 

  14. Birkbak, N. J. et al. Paradoxical relationship between chromosomal instability and survival outcome in cancer. Cancer Res. 71, 3447–3452 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 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 

  16. Holubcova, Z., Blayney, M., Elder, K. & Schuh, M. Human oocytes. Error-prone chromosome-mediated spindle assembly favors chromosome segregation defects in human oocytes. Science 348, 1143–1147 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Delhanty, J. D. et al. Detection of aneuploidy and chromosomal mosaicism in human embryos during preimplantation sex determination by fluorescent in situ hybridisation, (FISH). Hum. Mol. Genet. 2, 1183–1185 (1993).

    CAS  PubMed  Google Scholar 

  18. van Echten-Arends, J. et al. Chromosomal mosaicism in human preimplantation embryos: a systematic review. Hum. Reprod. Update 17, 620–627 (2011).

    PubMed  Google Scholar 

  19. Bazrgar, M., Gourabi, H., Valojerdi, M. R., Yazdi, P. E. & Baharvand, H. Self-correction of chromosomal abnormalities in human preimplantation embryos and embryonic stem cells. Stem Cells Dev. 22, 2449–2456 (2013).

    CAS  PubMed  Google Scholar 

  20. Bolton, H. et al. Mouse model of chromosome mosaicism reveals lineage-specific depletion of aneuploid cells and normal developmental potential. Nat. Commun. 7, 11165 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 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. USA 111, 13409–13414 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 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  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 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 

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

    PubMed  Google Scholar 

  26. Schoenfelder, K. P. et al. Indispensable pre-mitotic endocycles promote aneuploidy in the Drosophila rectum. Development 141, 3551–3560 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  28. Storchova, Z. & Kuffer, C. The consequences of tetraploidy and aneuploidy. J. Cell Sci. 121, 3859–3866 (2008).

    CAS  PubMed  Google Scholar 

  29. Taylor, A. M. et al. Genomic and functional approaches to understanding cancer aneuploidy. Cancer Cell 33, 676–689 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 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 

  31. 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 

  32. Levine, M. S. & Holland, A. J. The impact of mitotic errors on cell proliferation and tumorigenesis. Genes Dev. 32, 620–638 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Cheeseman, I. M. The kinetochore. Cold Spring Harb. Perspect. Biol. 6, a015826 (2014).

    PubMed  PubMed Central  Google Scholar 

  34. Lara-Gonzalez, P., Westhorpe, F. G. & Taylor, S. S. The spindle assembly checkpoint. Curr. Biol. 22, R966–R980 (2012).

    CAS  PubMed  Google Scholar 

  35. Lampson, M. A. & Grishchuk, E. L. Mechanisms to avoid and correct erroneous kinetochore–microtubule attachments. Biology (Basel) 6, 1 (2017).

    Google Scholar 

  36. Sansregret, L. & Swanton, C. The role of aneuploidy in cancer evolution. Cold Spring Harb. Perspect. Med. 7, a028373 (2017).

    PubMed  PubMed Central  Google Scholar 

  37. Simonetti, G., Bruno, S., Padella, A., Tenti, E. & Martinelli, G. Aneuploidy: cancer strength or vulnerability? Int. J. Cancer https://doi.org/10.1002/ijc.31718 (2018).

  38. Hernando, E. et al. Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic control. Nature 430, 797–802 (2004).

    CAS  PubMed  Google Scholar 

  39. 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 

  40. Cui, Y., Borysova, M. K., Johnson, J. O. & Guadagno, T. M. Oncogenic B-RafV600E induces spindle abnormalities, supernumerary centrosomes, and aneuploidy in human melanocytic cells. Cancer Res. 70, 675–684 (2010).

    CAS  PubMed  Google Scholar 

  41. Orr, B. & Compton, D. A. A double-edged sword: how oncogenes and tumor suppressor genes can contribute to chromosomal instability. Front. Oncol. 3, 164 (2013).

    PubMed  PubMed Central  Google Scholar 

  42. Conery, A. R. & Harlow, E. High-throughput screens in diploid cells identify factors that contribute to the acquisition of chromosomal instability. Proc. Natl Acad. Sci. USA 107, 15455–15460 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Meena, J. K. et al. Telomerase abrogates aneuploidy-induced telomere replication stress, senescence and cell depletion. EMBO J. 34, 1371–1384 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Knouse, K. A., Lopez, K. E., Bachofner, M. & Amon, A. Chromosome segregation fidelity in epithelia requires tissue architecture. Cell 175, 200–211 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Castedo, M. et al. Cell death by mitotic catastrophe: a molecular definition. Oncogene 23, 2825–2837 (2004).

    CAS  PubMed  Google Scholar 

  46. Janssen, A., Kops, G. J. & Medema, R. H. Elevating the frequency of chromosome mis-segregation as a strategy to kill tumor cells. Proc. Natl Acad. Sci. USA 106, 19108–19113 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Hinchcliffe, E. H. et al. Chromosome missegregation during anaphase triggers p53 cell cycle arrest through histone H3.3 Ser31 phosphorylation. Nat. Cell Biol. 18, 668–675 (2016).

    CAS  PubMed  Google Scholar 

  49. Santaguida, S. et al. Chromosome mis-segregation generates cell-cycle-arrested cells with complex karyotypes that are eliminated by the immune system. Dev. Cell 41, 638–651 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Soto, M. et al. p53 prohibits propagation of chromosome segregation errors that produce structural aneuploidies. Cell Rep. 19, 2423–2431 (2017).

    CAS  PubMed  Google Scholar 

  51. Lopez-Garcia, C. et al. BCL9L dysfunction impairs caspase-2 expression permitting aneuploidy tolerance in colorectal cancer. Cancer Cell 31, 79–93 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Sansregret, L. et al. APC/C dysfunction limits excessive cancer chromosomal instability. Cancer Discov. 7, 218–233 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Donnelly, N., Passerini, V., Durrbaum, 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Dodgson, S. E., Santaguida, S., Kim, S., Sheltzer, J. & Amon, A. The pleiotropic deubiquitinase Ubp3 confers aneuploidy tolerance. Genes Dev. 30, 2259–2271 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Michel, L. S. et al. MAD2 haplo-insufficiency causes premature anaphase and chromosome instability in mammalian cells. Nature 409, 355–359 (2001).

    CAS  PubMed  Google Scholar 

  57. Sotillo, R. et al. Mad2 overexpression promotes aneuploidy and tumorigenesis in mice. Cancer Cell 11, 9–23 (2007).

    CAS  PubMed  Google Scholar 

  58. Weaver, B. 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 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Ohashi, A. et al. Aneuploidy generates proteotoxic stress and DNA damage concurrently with p53-mediated post-mitotic apoptosis in SAC-impaired cells. Nat. Commun. 6, 7668 (2015).

    PubMed  Google Scholar 

  61. Fournier, R. E. A general high-efficiency procedure for production of microcell hybrids. Proc. Natl Acad. Sci. USA 78, 6349–6353 (1981).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 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 

  63. Stingele, S. et al. Global analysis of genome, transcriptome and proteome reveals the response to aneuploidy in human cells. Mol. Syst. Biol. 8, 608 (2012).

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Adikusuma, F., Williams, N., Grutzner, F., Hughes, J. & Thomas, P. Targeted deletion of an entire chromosome using CRISPR/Cas9. Mol. Ther. 25, 1736–1738 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Zuo, E. et al. CRISPR/Cas9-mediated targeted chromosome elimination. Genome Biol. 18, 224 (2017).

    PubMed  PubMed Central  Google Scholar 

  67. 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 

  68. 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 

  69. 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 

  70. Beach, R. R. et al. Aneuploidy causes non-genetic individuality. Cell 169, 229–242 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Naylor, R. M. & van Deursen, J. M. Aneuploidy in cancer and aging. Annu. Rev. Genet. 50, 45–66 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Zhu, J., Tsai, H.-J., Gordon, M. R. & Li, R. Cellular stress associated with aneuploidy. Dev. Cell 44, 420–431 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 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 

  74. 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 

  75. Ariyoshi, K. et al. Induction of genomic instability and activation of autophagy in artificial human aneuploid cells. Mutat. Res. 790, 19–30 (2016).

    CAS  PubMed  Google Scholar 

  76. 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 

  77. Gogendeau, D. et al. Aneuploidy causes premature differentiation of neural and intestinal stem cells. Nat. Commun. 6, 8894 (2015).

    CAS  PubMed  Google Scholar 

  78. Jonas, K., Liu, J., Chien, P. & Laub, M. T. Proteotoxic stress induces a cell-cycle arrest by stimulating Lon to degrade the replication initiator DnaA. Cell 154, 623–636 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Barr, A. R. et al. DNA damage during S-phase mediates the proliferation-quiescence decision in the subsequent G1 via p21 expression. Nat. Commun. 8, 14728 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Liu, X. et al. Trisomy eight in ES cells is a common potential problem in gene targeting and interferes with germ line transmission. Dev. Dyn. 209, 85–91 (1997).

    CAS  PubMed  Google Scholar 

  81. Ben-David, U. et al. Aneuploidy induces profound changes in gene expression, proliferation and tumorigenicity of human pluripotent stem cells. Nat. Commun. 5, 4825 (2014).

    CAS  PubMed  Google Scholar 

  82. Zhang, M. et al. Aneuploid embryonic stem cells exhibit impaired differentiation and increased neoplastic potential. EMBO J. 35, 2285–2300 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Selmecki, A., Forche, A. & Berman, J. Genomic plasticity of the human fungal pathogen Candida albicans. Eukaryot. Cell 9, 991–1008 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Rutledge, S. D. et al. Selective advantage of trisomic human cells cultured in non-standard conditions. Sci. Rep. 6, 22828 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Baker, D. E. et al. Adaptation to culture of human embryonic stem cells and oncogenesis in vivo. Nat. Biotechnol. 25, 207–215 (2007).

    CAS  PubMed  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

  88. Mao, R. et al. Primary and secondary transcriptional effects in the developing human Down syndrome brain and heart. Genome Biol. 6, R107 (2005).

    PubMed  PubMed Central  Google Scholar 

  89. Lockstone, H. E. et al. Gene expression profiling in the adult Down syndrome brain. Genomics 90, 647–660 (2007).

    CAS  PubMed  Google Scholar 

  90. Halevy, T., Biancotti, J. C., Yanuka, O., Golan-Lev, T. & Benvenisty, N. Molecular characterization of Down syndrome embryonic stem cells reveals a role for RUNX1 in neural differentiation. Stem Cell Rep. 7, 777–786 (2016).

    CAS  Google Scholar 

  91. Aziz, N. M. et al. Lifespan analysis of brain development, gene expression and behavioral phenotypes in the Ts1Cje, Ts65Dn and Dp(16)1/Yey mouse models of Down syndrome. Dis. Model. Mech. 11, dmm031013 (2018).

    PubMed  PubMed Central  Google Scholar 

  92. Penny, G. D., Kay, G. F., Sheardown, S. A., Rastan, S. & Brockdorff, N. Requirement for Xist in X chromosome inactivation. Nature 379, 131–137 (1996).

    CAS  PubMed  Google Scholar 

  93. Tartaglia, N. R., Howell, S., Sutherland, A., Wilson, R. & Wilson, L. A review of trisomy X (47,XXX). Orphanet J. Rare Dis. 5, 8 (2010).

    PubMed  PubMed Central  Google Scholar 

  94. Stenberg, P. et al. Buffering of segmental and chromosomal aneuploidies in Drosophila melanogaster. PLoS Genet. 5, e1000465 (2009).

    PubMed  PubMed Central  Google Scholar 

  95. Zhang, Y. et al. Expression in aneuploid Drosophila S2 cells. PLoS Biol. 8, e1000320 (2010).

    PubMed  PubMed Central  Google Scholar 

  96. Johansson, A. M., Stenberg, P., Bernhardsson, C. & Larsson, J. Painting of fourth and chromosome-wide regulation of the 4th chromosome in Drosophila melanogaster. EMBO J. 26, 2307–2316 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Gelbart, M. E. & Kuroda, M. I. Drosophila dosage compensation: a complex voyage to the X chromosome. Development 136, 1399–1410 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Hose, J. et al. Dosage compensation can buffer copy-number variation in wild yeast. eLife 4, e05462 (2015).

    PubMed Central  Google Scholar 

  99. Torres, E. M., Springer, M. & Amon, A. No current evidence for widespread dosage compensation in S. cerevisiae. eLife 5, e10996 (2016).

    PubMed  PubMed Central  Google Scholar 

  100. Tucker, C. et al. Transcriptional regulation on aneuploid chromosomes in divers Candida albicans mutants. Sci. Rep. 8, 1630 (2018).

    PubMed  PubMed Central  Google Scholar 

  101. Dephoure, N. et al. Quantitative proteomic analysis reveals posttranslational responses to aneuploidy in yeast. eLife 3, e03023 (2014).

    PubMed  PubMed Central  Google Scholar 

  102. Liu, Y. et al. Systematic proteome and proteostasis profiling in human trisomy 21 fibroblast cells. Nat. Commun. 8, 1212 (2017).

    PubMed  PubMed Central  Google Scholar 

  103. Vigano, C. et al. Quantitative proteomic and phosphoproteomic comparison of human colon cancer DLD-1 cells differing in ploidy and chromosome stability. Mol. Biol. Cell 29, 1031–1047 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. McShane, E. et al. Kinetic analysis of protein stability reveals age-dependent degradation. Cell 167, 803–815 (2016).

    CAS  PubMed  Google Scholar 

  105. 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 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  107. O’Duibhir, E. et al. Cell cycle population effects in perturbation studies. Mol. Syst. Biol. 10, 732 (2014).

    PubMed  PubMed Central  Google Scholar 

  108. 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 

  109. Durrbaum, 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 

  110. 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 

  111. 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 

  112. Stefani, M. & Dobson, C. M. Protein aggregation and aggregate toxicity: new insights into protein folding, misfolding diseases and biological evolution. J. Mol. Med. (Berl.) 81, 678–699 (2003).

    CAS  Google Scholar 

  113. Hanna, J. et al. Deubiquitinating enzyme Ubp6 functions noncatalytically to delay proteasomal degradation. Cell 127, 99–111 (2006).

    CAS  PubMed  Google Scholar 

  114. Santaguida, S. & Amon, A. Aneuploidy triggers a TFEB-mediated lysosomal stress response. Autophagy 11, 2383–2384 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Nicholson, J. M. et al. Chromosome mis-segregation and cytokinesis failure in trisomic human cells. eLife 4, e05068 (2015).

    PubMed Central  Google Scholar 

  117. Passerini, V. et al. The presence of extra chromosomes leads to genomic instability. Nat. Commun. 7, 10754 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Sharma, K. et al. Quantitative proteomics reveals that Hsp90 inhibition preferentially targets kinases and the DNA damage response. Mol. Cell. Proteomics 11, M111.014654 (2012).

    PubMed  Google Scholar 

  119. Spurgers, K. B. et al. Identification of cell cycle regulatory genes as principal targets of p53-mediated transcriptional repression. J. Biol. Chem. 281, 25134–25142 (2006).

    CAS  PubMed  Google Scholar 

  120. Tan, Y. H., Schneider, E. L., Tischfield, J. & Epstein, C. J. & Ruddle, F. H. Human chromosome 21 dosage: effect on the expression of the interferon induced antiviral state. Science 186, 61–63 (1974).

    CAS  PubMed  Google Scholar 

  121. Iwamoto, T. et al. Influences of interferon-γ on cell proliferation and interleukin-6 production in Down syndrome derived fibroblasts. Arch. Oral Biol. 54, 963–969 (2009).

    CAS  PubMed  Google Scholar 

  122. Sullivan, K. D. et al. Trisomy 21 consistently activates the interferon response. eLife 5, e16220 (2016).

    PubMed  PubMed Central  Google Scholar 

  123. Ling, K. H. et al. Functional transcriptome analysis of the postnatal brain of the Ts1Cje mouse model for Down syndrome reveals global disruption of interferon-related molecular networks. BMC Genomics 15, 624 (2014).

    PubMed  PubMed Central  Google Scholar 

  124. Tanaka, M. H. et al. Expression of interferon-γ, interferon-α and related genes in individuals with Down syndrome and periodontitis. Cytokine 60, 875–881 (2012).

    CAS  PubMed  Google Scholar 

  125. Maroun, L. E. Interferon action and chromosome 21 trisomy (Down syndrome): 15 years later. J. Theor. Biol. 181, 41–46 (1996).

    CAS  PubMed  Google Scholar 

  126. Sun, L., Wu, J., Du, F., Chen, X. & Chen, Z. J. Cyclic GMP–AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway. Science 339, 786–791 (2013).

    CAS  PubMed  Google Scholar 

  127. Lan, Y. Y., Londono, D., Bouley, R., Rooney, M. S. & Hacohen, N. Dnase2a deficiency uncovers lysosomal clearance of damaged nuclear DNA via autophagy. Cell Rep. 9, 180–192 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Mackenzie, K. J. et al. cGAS surveillance of micronuclei links genome instability to innate immunity. Nature 548, 461–465 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Harding, S. M. et al. Mitotic progression following DNA damage enables pattern recognition within micronuclei. Nature 548, 466–470 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Bartsch, K. et al. Absence of RNase H2 triggers generation of immunogenic micronuclei removed by autophagy. Hum. Mol. Genet. 26, 3960–3972 (2017).

    CAS  PubMed  Google Scholar 

  131. Gasser, S., Orsulic, S., Brown, E. J. & Raulet, D. H. The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor. Nature 436, 1186–1190 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Rodier, F. et al. Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion. Nat. Cell Biol. 11, 973–979 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Cohen, I. et al. IL-1α is a DNA damage sensor linking genotoxic stress signaling to sterile inflammation and innate immunity. Sci. Rep. 5, 14756 (2015).

    CAS  PubMed  Google Scholar 

  134. Andriani, G. A. et al. Whole chromosome instability induces senescence and promotes SASP. Sci. Rep. 6, 35218 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Yang, H., Wang, H., Ren, J., Chen, Q. & Chen, Z. J. cGAS is essential for cellular senescence. Proc. Natl Acad. Sci. USA 114, E4612–E4620 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Hardy, P. A. & Zacharias, H. Reappraisal of the Hansemann–Boveri hypothesis on the origin of tumors. Cell Biol. Int. 29, 983–992 (2005).

    PubMed  Google Scholar 

  137. Knouse, K. A., Davoli, T., Elledge, S. J. & Amon, A. Aneuploidy in cancer: Seq-ing answers to old questions. Annu. Rev. Cancer Biol. 1, 335–354 (2017).

    Google Scholar 

  138. Sheltzer, J. M. et al. Single-chromosome gains commonly function as tumor suppressors. Cancer Cell 31, 240–255 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Iwanaga, Y. et al. Heterozygous deletion of mitotic arrest-deficient protein 1 (MAD1) increases the incidence of tumors in mice. Cancer Res. 67, 160–166 (2007).

    CAS  PubMed  Google Scholar 

  140. Dai, W. et al. Slippage of mitotic arrest and enhanced tumor development in mice with BubR1 haploinsufficiency. Cancer Res. 64, 440–445 (2004).

    CAS  PubMed  Google Scholar 

  141. 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 

  142. Baker, D. J. et al. Early aging-associated phenotypes in Bub3/Rae1 haploinsufficient mice. J. Cell Biol. 172, 529–540 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Hasle, H., Clemmensen, I. H. & Mikkelsen, M. Risks of leukaemia and solid tumours in individuals with Down’s syndrome. Lancet 355, 165–169 (2000).

    CAS  PubMed  Google Scholar 

  144. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

    CAS  PubMed  Google Scholar 

  145. Dai, C. & Sampson, S. B. HSF1: guardian of proteostasis in cancer. Trends Cell Biol. 26, 17–28 (2016).

    CAS  PubMed  Google Scholar 

  146. Perera, R. M. et al. Transcriptional control of autophagy–lysosome function drives pancreatic cancer metabolism. Nature 524, 361–365 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Sidera, K. & Patsavoudi, E. HSP90 inhibitors: current development and potential in cancer therapy. Recent Pat. Anticancer Drug Discov. 9, 1–20 (2014).

    CAS  PubMed  Google Scholar 

  148. Bastola, P., Oien, D. B., Cooley, M. & Chien, J. Emerging cancer therapeutic targets in protein homeostasis. AAPS J. 20, 94 (2018).

    PubMed  Google Scholar 

  149. Mahalingam, D. et al. Targeting HSP90 for cancer therapy. Br. J. Cancer 100, 1523–1529 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Whitesell, L. & Lindquist, S. L. HSP90 and the chaperoning of cancer. Nat. Rev. Cancer 5, 761–772 (2005).

    CAS  PubMed  Google Scholar 

  151. Burrell, R. A. et al. Replication stress links structural and numerical cancer chromosomal instability. Nature 494, 492–496 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Chan, Y. W., Fugger, K. & West, S. C. Unresolved recombination intermediates lead to ultra-fine anaphase bridges, chromosome breaks and aberrations. Nat. Cell Biol. 20, 92–103 (2018).

    CAS  PubMed  Google Scholar 

  153. Duesberg, P., Rausch, C., Rasnick, D. & Hehlmann, R. Genetic instability of cancer cells is proportional to their degree of aneuploidy. Proc. Natl Acad. Sci. USA 95, 13692–13697 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Davoli, T., Uno, H., Wooten, E. C. & Elledge, S. J. Tumor aneuploidy correlates with markers of immune evasion and with reduced response to immunotherapy. Science 355, eaaf8399 (2017).

    PubMed  PubMed Central  Google Scholar 

  155. Davoli, T. et al. Cumulative haploinsufficiency and triplosensitivity drive aneuploidy patterns and shape the cancer genome. Cell 155, 948–962 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Kops, G. J., Foltz, D. R. & Cleveland, D. W. Lethality to human cancer cells through massive chromosome loss by inhibition of the mitotic checkpoint. Proc. Natl Acad. Sci. USA 101, 8699–8704 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. Godek, K. M. et al. Chromosomal instability affects the tumorigenicity of glioblastoma tumor-initiating cells. Cancer Discov. 6, 532–545 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  158. Beaupere, C. et al. Genetic screen identifies adaptive aneuploidy as a key mediator of ER stress resistance in yeast. Proc. Natl Acad. Sci. USA 15, 9586–9591 (2018).

    Google Scholar 

  159. Chen, G., Bradford, W. D., Seidel, C. W. & Li, R. Hsp90 stress potentiates rapid cellular adaptation through induction of aneuploidy. Nature 482, 246–250 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  160. 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 

  161. Kaya, A. et al. Adaptive aneuploidy protects against thiol peroxidase deficiency by increasing respiration via key mitochondrial proteins. Proc. Natl Acad. Sci. USA 112, 10685–10690 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Ryu, H.-Y., Wilson, N. R., Mehta, S., Hwang, S. S. & Hochstrasser, M. Loss of the SUMO protease Ulp2 triggers a specific multichromosome aneuploidy. Genes Dev. 30, 1881–1894 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  163. Millet, C., Ausiannikava, D., Le Bihan, T., Granneman, S. & Makovets, S. Cell populations can use aneuploidy to survive telomerase insufficiency. Nat. Commun. 6, 8664 (2015).

    CAS  PubMed  Google Scholar 

  164. Hughes, T. R. et al. Widespread aneuploidy revealed by DNA microarray expression profiling. Nat. Genet. 25, 333–337 (2000).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  166. Vesely, M. D., Kershaw, M. H., Schreiber, R. D. & Smyth, M. J. Natural innate and adaptive immunity to cancer. Annu. Rev. Immunol. 29, 235–271 (2011).

    CAS  PubMed  Google Scholar 

  167. Dunn, G. P., Bruce, A. T., Ikeda, H., Old, L. J. & Schreiber, R. D. Cancer immunoediting: from immunosurveillance to tumor escape. Nat. Immunol. 3, 991–998 (2002).

    CAS  PubMed  Google Scholar 

  168. Schreiber, R. D., Old, L. J. & Smyth, M. J. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science 331, 1565–1570 (2011).

    CAS  PubMed  Google Scholar 

  169. McGranahan, N. et al. Allele-specific HLA loss and immune escape in lung cancer evolution. Cell 171, 1259–1271 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The work on aneuploidy is supported by the German Research Foundation, grant agreement STO918/5-1 to Z.S.

Author information

Authors and Affiliations

Authors

Contributions

Both authors contributed equally.

Corresponding author

Correspondence to Zuzana Storchová.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chunduri, N.K., Storchová, Z. The diverse consequences of aneuploidy. Nat Cell Biol 21, 54–62 (2019). https://doi.org/10.1038/s41556-018-0243-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41556-018-0243-8

This article is cited by

Search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer