Aneuploidy and Protein Homeostatic Imbalance


Aneuploidy is an aberrant condition that a cell harbours incorrect chromosome numbers or identities often resulted from mitotic errors. Aneuploidy impacts cellular functions, developmental programme and affects individual fitness, and leads to examples such as Down syndrome and tumours. The gain or loss of large amount of genes caused by chromosome copy‐number changes can alter metabolic programmes and protein homeostasis. In most circumstances, the elicited stress responses which are detrimental to cellular and organismal fitness. However, in cancer cells, same stresses may be beneficial to pose adaptive potentials. In this article, the paradox of aneuploidy is discussed, and the triggering of aneuploidy‐associated protein homeostatic imbalance which may serve as a strategy to treat cancer.

Key Concepts

  • Aneuploidy is a situation that a cell harbours aberrant number of chromosomes that is not a multiple of the haploid complement.
  • Aneuploidy is mostly caused by mitotic errors and is irreversible in cells.
  • Aneuploidy generally resulted in adverse effect in both cellular and organismal levels; however, in stress conditions it may facilitate adaptation.
  • Aneuploidy causes protein homeostatic imbalance; thus, the proteotoxic property in cancer cells may apply as treatment for tumours.

Keywords: aneuploidy; chaperone; chromosome instability; protein homeostatic imbalance; protein quality control

Figure 1. The spindle assembly checkpoint system. Spindle assembly checkpoint (SAC) is employed during cell cycles to ensure that the sister chromatids are correctly aligned before cell division. Several proteins, including BUB1, BUB3 and MAD2 are involved in SAC, and mainly act as inhibitors for APC/C. Once microtubule‐kinetochore attachments are properly built, CDC20/APC/C initiates the degradation of securin, and releases active separase to hydrolyse cohesin, further separates sister chromatids.
Figure 2. The protein quality control system. The protein homeostasis maintenance is executed by protein quality control system, which includes protein synthesis, folding, trafficking and degradation processes. Chaperones mediate the co‐translational folding of nascent polypeptides and post‐translational refolding at some circumstances. For unfolded, misfolded, or aggregation proteins that are targeted for degradation, chaperones can as well assist their presentation to the ubiquitin‐proteasome system (UPS) and autophagy system for irreversibly proteolytic degradation.
Figure 3. The proteotoxic stress caused by aneuploidy. In euploid cells, protein quality control system is active to maintain correct stoichiometry for functional complexes composed by subunit A and B. Subunit A and B are encoded by chromosome 1 and 2, respectively. In aneuploidy situation with additional chromosome 2, extra subunit B fails to complex with subunit A for functional dimer, thus is structurally unstable in the bulk and waits for degradation. A vast gain or loss of gene products will challenge and deplete chaperones, the UPS and autophagy system from the physiological tasks, therefore eventually cause protein homeostatic imbalance.


Baek KH, Zaslavsky A, Lynch RC, et al. (2009) Down's syndrome suppression of tumour growth and the role of the calcineurin inhibitor DSCR1. Nature 459: 1126–1130.

Baker DJ, Jin F, Jeganathan KB and van Deursen JM (2009) Whole chromosome instability caused by Bub1 insufficiency drives tumorigenesis through tumor suppressor gene loss of heterozygosity. Cancer Cell 16: 475–486.

Balch WE, Morimoto RI, Dillin A and Kelly JW (2008) Adapting proteostasis for disease intervention. Science 319: 916–919.

Balmain A (2001) Cancer genetics: from Boveri and Mendel to microarrays. Nature Reviews Cancer 1: 77–82.

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

Duijf PH and Benezra R (2013) The cancer biology of whole‐chromosome instability. Oncogene 32: 4727–4736.

Duncan AW, Taylor MH, Hickey RD, et al. (2010) The ploidy conveyor of mature hepatocytes as a source of genetic variation. Nature 467: 707–710.

Edlund T and Normark S (1981) Recombination between short DNA homologies causes tandem duplication. Nature 292: 269–271.

Gartler SM (2006) The chromosome number in humans: a brief history. Nature Reviews Genetics 7: 655–660.

Geiler‐Samerotte KA, Dion MF, Budnik BA, et al. (2011) Misfolded proteins impose a dosage‐dependent fitness cost and trigger a cytosolic unfolded protein response in yeast. Proceedings of the National Academy of Sciences of the United States of America 108: 680–685.

Hartl FU, Bracher A and Hayer‐Hartl M (2011) Molecular chaperones in protein folding and proteostasis. Nature 475: 324–332.

Hasle H, Clemmensen IH and Mikkelsen M (2000) Risks of leukaemia and solid tumours in individuals with Down's syndrome. Lancet 355: 165–169.

Hassold T, Abruzzo M, Adkins K, et al. (1996) Human aneuploidy: incidence, origin, and etiology. Environmental and Molecular Mutagenesis 28: 167–175.

Hodgkin J (2005) Karyotype, ploidy, and gene dosage. WormBook 1‐9.

Holland AJ and Cleveland DW (2012a) Losing balance: the origin and impact of aneuploidy in cancer. EMBO Reports 13: 501–514.

Kaizu K, Moriya H and Kitano H (2010) Fragilities caused by dosage imbalance in regulation of the budding yeast cell cycle. PLoS Genetics 6: e1000919.

Lengauer C, Kinzler KW and Vogelstein B (1998) Genetic instabilities in human cancers. Nature 396: 643–649.

Li M, Fang X, Baker DJ, et al. (2010) The ATM‐p53 pathway suppresses aneuploidy‐induced tumorigenesis. Proceedings of the National Academy of Sciences of the United States of America 107: 4153–4158.

Lindsley DL, Sandler L, Baker BS, et al. (1972) Segmental aneuploidy and the genetic gross structure of the Drosophila genome. Genetics 71: 157–184.

Michel LS, Liberal V, Chatterjee A, et al. (2001) MAD2 haplo‐insufficiency causes premature anaphase and chromosome instability in mammalian cells. Nature 409: 355–359.

Monje‐Casas F, Prabhu VR, Lee BH, Boselli M and Amon A (2007) Kinetochore orientation during meiosis is controlled by Aurora B and the monopolin complex. Cell 128: 477–490.

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

Olzscha H, Schermann SM, Woerner AC, et al. (2011) Amyloid‐like aggregates sequester numerous metastable proteins with essential cellular functions. Cell 144: 67–78.

Oromendia AB, Dodgson SE and Amon A (2012) Aneuploidy causes proteotoxic stress in yeast. Genes & Development 26: 2696–2708.

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

Powers ET, Morimoto RI, Dillin A, Kelly JW and Balch WE (2009) Biological and chemical approaches to diseases of proteostasis deficiency. Annual Review of Biochemistry 78: 959–991.

Ricke RM and van Deursen JM (2013) Aneuploidy in health, disease, and aging. The Journal of Cell Biology 201: 11–21.

Santagata S, Mendillo ML, Tang YC, et al. (2013) Tight coordination of protein translation and HSF1 activation supports the anabolic malignant state. Science 341: 1238303.

Schvartzman JM, Duijf PH, Sotillo R, Coker C and Benezra R (2011) Mad2 is a critical mediator of the chromosome instability observed upon Rb and p53 pathway inhibition. Cancer Cell 19: 701–714.

Sheltzer JM, Blank HM, Pfau SJ, et al. (2011) Aneuploidy drives genomic instability in yeast. Science 333: 1026–1030.

Stingele S, Stoehr G, Peplowska K, et al. (2012) Global analysis of genome, transcriptome and proteome reveals the response to aneuploidy in human cells. Molecular Systems Biology 8: 608.

Stingele S, Stoehr G and Storchova Z (2013) Activation of autophagy in cells with abnormal karyotype. Autophagy 9: 246–248.

Tang YC and Amon A (2013) Gene copy‐number alterations: a cost‐benefit analysis. Cell 152: 394–405.

Tang YC, Williams BR, Siegel JJ and Amon A (2011) Identification of aneuploidy‐selective antiproliferation compounds. Cell 144: 499–512.

Torres EM, Sokolsky T, Tucker CM, et al. (2007) Effects of aneuploidy on cellular physiology and cell division in haploid yeast. Science 317: 916–924.

Torres EM, Dephoure N, Panneerselvam A, et al. (2010) Identification of aneuploidy‐tolerating mutations. Cell 143: 71–83.

Vander Heiden MG, Cantley LC and Thompson CB (2009) Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324: 1029–1033.

Vavouri T, Semple JI, Garcia‐Verdugo R and Lehner B (2009) Intrinsic protein disorder and interaction promiscuity are widely associated with dosage sensitivity. Cell 138: 198–208.

Weaver BA and Cleveland DW (2008) The aneuploidy paradox in cell growth and tumorigenesis. Cancer Cell 14: 431–433.

Williams BR, Prabhu VR, Hunter KE, et al. (2008) Aneuploidy affects proliferation and spontaneous immortalization in mammalian cells. Science 322: 703–709.

Yang Q, Rasmussen SA and Friedman JM (2002) Mortality associated with Down's syndrome in the USA from 1983 to 1997: a population‐based study. Lancet 359: 1019–1025.

Yona AH, Manor YS, Herbst RH, et al. (2012) Chromosomal duplication is a transient evolutionary solution to stress. Proceedings of the National Academy of Sciences of the United States of America 109: 21010–21015.

Zhu J, Pavelka N, Bradford WD, Rancati G and Li R (2012) Karyotypic determinants of chromosome instability in aneuploid budding yeast. PLoS Genetics 8: e1002719.

Further Reading

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

Gordon DJ, Resio B and Pellman D (2012) Causes and consequences of aneuploidy in cancer. Nature Reviews Genetics 13: 189–203.

Holland AJ and Cleveland DW (2012b) Losing balance: the origin and impact of aneuploidy in cancer. EMBO Report. 13: 501–514.

London N and Biggins S (2014) Signalling dynamics in the spindle checkpoint response. Nature Reviews Molecular Cell Biology 15: 736–748.

Pfau SJ and Amon A (2012) Chromosomal instability and aneuploidy in cancer: from yeast to man. EMBO Report. 13: 515–527.

Siegel JJ and Amon A (2012) New insights into the troubles of aneuploidy. Annual Review of Cell and Developmental Biology 28: 189–214.

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Tang, Yun‐Chi(Jul 2015) Aneuploidy and Protein Homeostatic Imbalance. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0025987]