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Cytokinesis defects and cancer

Nature Reviews Cancer volume 19, pages 32–45 (2019)Cite this article

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Abstract

Whole-genome and centrosome duplication as a consequence of cytokinesis failure can drive tumorigenesis in experimental model systems. However, whether cytokinesis failure is in fact an important cause of human cancers has remained unclear. In this Review, we summarize evidence that whole-genome-doubling events are frequently observed in human cancers and discuss the contribution that cytokinesis defects can make to tumorigenesis. We provide an overview of the potential causes of cytokinesis failure and discuss how tetraploid cells that are generated through cytokinesis defects are used in cancer as a transitory state on the route to aneuploidy. Finally, we discuss how cytokinesis defects can facilitate genetic diversification within the tumour to promote cancer development and could constitute the path of least resistance in tumour evolution.

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Fig. 1: The stages of cytokinesis.
Fig. 2: From tetraploidy to aneuploidy.
Fig. 3: Causes of cytokinesis failure.
Fig. 4: The different fates of a tetraploid G1 cell.

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References

  1. Glotzer, M. Cytokinesis in metazoa and fungi. Cold Spring Harb. Perspect. Biol. 9, a022343 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  2. Green, R. A., Paluch, E. & Oegema, K. Cytokinesis in animal cells. Annu. Rev. Cell Dev. Biol. 28, 29–58 (2012).

    Article  CAS  PubMed  Google Scholar 

  3. Duijf, P. H., Schultz, N. & Benezra, R. Cancer cells preferentially lose small chromosomes. Int. J. Cancer 132, 2316–2326 (2013).

    Article  CAS  PubMed  Google Scholar 

  4. Weaver, B. A. & Cleveland, D. W. Aneuploidy: instigator and inhibitor of tumorigenesis. Cancer Res. 67, 10103–10105 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Bielski, C. M. et al. Genome doubling shapes the evolution and prognosis of advanced cancers. Nat. Genet. 50, 1189–1195 (2018). This paper sequences a large number of primary tumours to demonstrate that genome-doubling events are very common in human cancer.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Carter, S. L. et al. Absolute quantification of somatic DNA alterations in human cancer. Nat. Biotechnol. 30, 413–421 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. de Bruin, E. C. et al. Spatial and temporal diversity in genomic instability processes defines lung cancer evolution. Science 346, 251–256 (2014). This study nicely describes the genome evolution of lung cancer as determined by deep sequencing and demonstrates that subclonal diversification is driven by heterogeneous genetic instability.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Galipeau, P. C. et al. 17p (p53) allelic losses, 4N (G2/tetraploid) populations, and progression to aneuploidy in Barrett’s esophagus. Proc. Natl Acad. Sci. USA 93, 7081–7084 (1996). This is a landmark study into Barrett oesophagus that provides compelling evidence for tetraploidy as an early event in tumorigenesis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Imkie, M., Davis, M. K., Persons, D. L. & Cunningham, M. T. Biphasic acute myeloid leukemia with near-tetraploidy and immunophenotypic transformation. Arch. Pathol. Lab. Med. 128, 448–451 (2004).

    PubMed  Google Scholar 

  10. Olaharski, A. J. et al. Tetraploidy and chromosomal instability are early events during cervical carcinogenesis. Carcinogenesis 27, 337–343 (2006).

    Article  CAS  PubMed  Google Scholar 

  11. Shackney, S. E. et al. Model for the genetic evolution of human solid tumors. Cancer Res. 49, 3344–3354 (1989).

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Watanabe, A. et al. Near-triploidy and near-tetraploidy in hematological malignancies and mutation of the p53 gene. Clin. Lab. Haematol. 26, 25–30 (2004).

    Article  CAS  PubMed  Google Scholar 

  15. Zack, T. I. et al. Pan-cancer patterns of somatic copy number alteration. Nat. Genet. 45, 1134–1140 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Duelli, D. M. et al. A virus causes cancer by inducing massive chromosomal instability through cell fusion. Curr. Biol. 17, 431–437 (2007).

    Article  CAS  PubMed  Google Scholar 

  17. Fujiwara, T. et al. Cytokinesis failure generating tetraploids promotes tumorigenesis in p53-null cells. Nature 437, 1043–1047 (2005). This study provides the first direct evidence that cytokinesis failure promotes tumorigenesis.

    Article  CAS  PubMed  Google Scholar 

  18. Ganem, N. J., Godinho, S. A. & Pellman, D. A mechanism linking extra centrosomes to chromosomal instability. Nature 460, 278–282 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Lengauer, C., Kinzler, K. W. & Vogelstein, B. Genetic instabilities in human cancers. Nature 396, 643–649 (1998).

    Article  CAS  PubMed  Google Scholar 

  20. Nguyen, H. G. et al. Deregulated Aurora-B induced tetraploidy promotes tumorigenesis. FASEB J. 23, 2741–2748 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Silkworth, W. T., Nardi, I. K., Scholl, L. M. & Cimini, D. Multipolar spindle pole coalescence is a major source of kinetochore mis-attachment and chromosome mis-segregation in cancer cells. PLOS ONE 4, e6564 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Storchova, Z. & Pellman, D. From polyploidy to aneuploidy, genome instability and cancer. Nat. Rev. Mol. Cell Biol. 5, 45–54 (2004).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Zasadil, L. M., Britigan, E. M. & Weaver, B. A. 2n or not 2n: aneuploidy, polyploidy and chromosomal instability in primary and tumor cells. Semin. Cell Dev. Biol. 24, 370–379 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Silk, A. D. et al. Chromosome missegregation rate predicts whether aneuploidy will promote or suppress tumors. Proc. Natl Acad. Sci. USA 110, E4134–E4141 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kishi, K., Sasaki, T., Kuroda, S., Itoh, T. & Takai, Y. Regulation of cytoplasmic division of Xenopus embryo by rho p21 and its inhibitory GDP/GTP exchange protein (rho GDI). J. Cell Biol. 120, 1187–1195 (1993).

    Article  CAS  PubMed  Google Scholar 

  27. Petronczki, M., Glotzer, M., Kraut, N. & Peters, J. M. Polo-like kinase 1 triggers the initiation of cytokinesis in human cells by promoting recruitment of the RhoGEF Ect2 to the central spindle. Dev. Cell 12, 713–725 (2007). This study nicely shows how spatiotemporal control of furrow ingression is mediated through PLK1.

    Article  CAS  PubMed  Google Scholar 

  28. Kim, J. E., Billadeau, D. D. & Chen, J. The tandem BRCT domains of Ect2 are required for both negative and positive regulation of Ect2 in cytokinesis. J. Biol. Chem. 280, 5733–5739 (2005).

    Article  CAS  PubMed  Google Scholar 

  29. Kosako, H. et al. Rho-kinase/ROCK is involved in cytokinesis through the phosphorylation of myosin light chain and not ezrin/radixin/moesin proteins at the cleavage furrow. Oncogene 19, 6059–6064 (2000).

    Article  CAS  PubMed  Google Scholar 

  30. Kitagawa, M. & Lee, S. H. The chromosomal passenger complex (CPC) as a key orchestrator of orderly mitotic exit and cytokinesis. Front. Cell Dev. Biol. 3, 14 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  31. Kitagawa, M., Fung, S. Y., Onishi, N., Saya, H. & Lee, S. H. Targeting Aurora B to the equatorial cortex by MKlp2 is required for cytokinesis. PLOS ONE 8, e64826 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Mollinari, C. et al. Ablation of PRC1 by small interfering RNA demonstrates that cytokinetic abscission requires a central spindle bundle in mammalian cells, whereas completion of furrowing does not. Mol. Biol. Cell 16, 1043–1055 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Lacroix, B. & Maddox, A. S. Cytokinesis, ploidy and aneuploidy. J. Pathol. 226, 338–351 (2012).

    Article  CAS  PubMed  Google Scholar 

  34. Wong, C. & Stearns, T. Mammalian cells lack checkpoints for tetraploidy, aberrant centrosome number, and cytokinesis failure. BMC Cell Biol. 6, 6 (2005).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Shi, Q. & King, R. W. Chromosome nondisjunction yields tetraploid rather than aneuploid cells in human cell lines. Nature 437, 1038–1042 (2005).

    Article  CAS  PubMed  Google Scholar 

  36. Thomas, P. et al. Buccal micronucleus cytome assay. Nat. Protoc. 4, 825–837 (2009).

    Article  CAS  PubMed  Google Scholar 

  37. Ramirez, A. & Saldanha, P. H. Micronucleus investigation of alcoholic patients with oral carcinomas. Genet. Mol. Res. 1, 246–260 (2002). This study shows that there is a high percentage of binucleated cells in oral mucosa, suggesting that cytokinesis failures may be common in the human body or at least in this particular tissue.

    PubMed  Google Scholar 

  38. Nersesyan, A., Kundi, M., Atefie, K., Schulte-Hermann, R. & Knasmuller, S. Effect of staining procedures on the results of micronucleus assays with exfoliated oral mucosa cells. Cancer Epidemiol. Biomarkers Prev. 15, 1835–1840 (2006).

    Article  CAS  PubMed  Google Scholar 

  39. Celik, A. & Kanik, A. Genotoxicity of occupational exposure to wood dust: micronucleus frequency and nuclear changes in exfoliated buccal mucosa cells. Environ. Mol. Mutag. 47, 693–698 (2006).

    Article  CAS  Google Scholar 

  40. Celik, A., Yildirim, S., Ekinci, S. Y. & Tasdelen, B. Bio-monitoring for the genotoxic assessment in road construction workers as determined by the buccal micronucleus cytome assay. Ecotoxicol. Environ. Saf. 92, 265–270 (2013).

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Kudryavtsev, B. N., Kudryavtseva, M. V., Sakuta, G. A. & Stein, G. I. Human hepatocyte polyploidization kinetics in the course of life cycle. Virchows Arch. B 64, 387–393 (1993).

    Article  CAS  PubMed  Google Scholar 

  44. Wang, M. J., Chen, F., Lau, J. T. Y. & Hu, Y. P. Hepatocyte polyploidization and its association with pathophysiological processes. Cell Death Dis. 8, e2805 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Guidotti, J. E. et al. Liver cell polyploidization: a pivotal role for binuclear hepatocytes. J. Biol. Chem. 278, 19095–19101 (2003).

    Article  CAS  PubMed  Google Scholar 

  46. Margall-Ducos, G., Celton-Morizur, S., Couton, D., Bregerie, O. & Desdouets, C. Liver tetraploidization is controlled by a new process of incomplete cytokinesis. J. Cell Sci. 120, 3633–3639 (2007).

    Article  CAS  PubMed  Google Scholar 

  47. Jensen, C. G., Jensen, L. C., Rieder, C. L., Cole, R. W. & Ault, J. G. Long crocidolite asbestos fibers cause polyploidy by sterically blocking cytokinesis. Carcinogenesis 17, 2013–2021 (1996). This study provides evidence that asbestos can promote tumorigenesis by induction of cytokinesis failure.

    Article  CAS  PubMed  Google Scholar 

  48. Overholtzer, M. et al. A nonapoptotic cell death process, entosis, that occurs by cell-in-cell invasion. Cell 131, 966–979 (2007). This paper describes the discovery of entosis.

    Article  CAS  PubMed  Google Scholar 

  49. Krajcovic, M. et al. A non-genetic route to aneuploidy in human cancers. Nat. Cell Biol. 13, 324–330 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Mullins, J. M. & Biesele, J. J. Terminal phase of cytokinesis in D-98s cells. J. Cell Biol. 73, 672–684 (1977).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Norden, C. et al. The NoCut pathway links completion of cytokinesis to spindle midzone function to prevent chromosome breakage. Cell 125, 85–98 (2006).

    Article  CAS  PubMed  Google Scholar 

  52. Steigemann, P. et al. Aurora B-mediated abscission checkpoint protects against tetraploidization. Cell 136, 473–484 (2009).

    Article  PubMed  CAS  Google Scholar 

  53. Mierzwa, B. & Gerlich, D. W. Cytokinetic abscission: molecular mechanisms and temporal control. Dev. Cell 31, 525–538 (2014).

    Article  CAS  PubMed  Google Scholar 

  54. Ichijima, Y. et al. DNA lesions induced by replication stress trigger mitotic aberration and tetraploidy development. PLOS ONE 5, e8821 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. 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). This study describes the discovery of a distinct class of ultrafine DNA bridges (UFBs), namely, homologous recombination UFBs, that are converted into chromosome fusions when cytokinesis proceeds before they have been resolved.

    Article  CAS  PubMed  Google Scholar 

  56. Germann, S. M. et al. TopBP1/Dpb11 binds DNA anaphase bridges to prevent genome instability. J. Cell Biol. 204, 45–59 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Caldwell, C. M., Green, R. A. & Kaplan, K. B. APC mutations lead to cytokinetic failures in vitro and tetraploid genotypes in Min mice. J. Cell Biol. 178, 1109–1120 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Daniels, M. J., Wang, Y., Lee, M. & Venkitaraman, A. R. Abnormal cytokinesis in cells deficient in the breast cancer susceptibility protein BRCA2. Science 306, 876–879 (2004).

    Article  CAS  PubMed  Google Scholar 

  59. Sinha, S. et al. Von Hippel-Lindau gene product directs cytokinesis: a new tumor suppressor function. J. Cell Sci. 124, 2132–2142 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Yang, X. et al. LATS1 tumour suppressor affects cytokinesis by inhibiting LIMK1. Nat. Cell Biol. 6, 609–617 (2004).

    Article  CAS  PubMed  Google Scholar 

  61. St John, M. A. et al. Mice deficient of Lats1 develop soft-tissue sarcomas, ovarian tumours and pituitary dysfunction. Nat. Genet. 21, 182–186 (1999).

    Article  Google Scholar 

  62. Sharif, A. A. D. & Hergovich, A. The NDR/LATS protein kinases in immunology and cancer biology. Semin. Cancer Biol. 48, 104–114 (2018).

    Article  CAS  PubMed  Google Scholar 

  63. Fields, A. P. & Justilien, V. The guanine nucleotide exchange factor (GEF) Ect2 is an oncogene in human cancer. Adv. Enzyme Regul. 50, 190–200 (2010).

    Article  PubMed  Google Scholar 

  64. Normand, G. & King, R. W. Understanding cytokinesis failure. Adv. Exp. Med. Biol. 676, 27–55 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Justilien, V. & Fields, A. P. Ect2 links the PKCiota-Par6alpha complex to Rac1 activation and cellular transformation. Oncogene 28, 3597–3607 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Miki, T., Smith, C. L., Long, J. E., Eva, A. & Fleming, T. P. Oncogene ect2 is related to regulators of small GTP-binding proteins. Nature 362, 462–465 (1993).

    Article  CAS  PubMed  Google Scholar 

  67. Saito, S. et al. Deregulation and mislocalization of the cytokinesis regulator ECT2 activate the Rho signaling pathways leading to malignant transformation. J. Biol. Chem. 279, 7169–7179 (2004).

    Article  CAS  PubMed  Google Scholar 

  68. Hirata, D. et al. Involvement of epithelial cell transforming sequence-2 oncoantigen in lung and esophageal cancer progression. Clin. Cancer Res. 15, 256–266 (2009).

    Article  CAS  PubMed  Google Scholar 

  69. Luo, Y. et al. Elevated expression of ECT2 predicts unfavorable prognosis in patients with colorectal cancer. Biomed. Pharmacother. 73, 135–139 (2015).

    Article  CAS  PubMed  Google Scholar 

  70. Salhia, B. et al. The guanine nucleotide exchange factors trio, Ect2, and Vav3 mediate the invasive behavior of glioblastoma. Am. J. Pathol. 173, 1828–1838 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Sano, M. et al. Expression level of ECT2 proto-oncogene correlates with prognosis in glioma patients. Oncol. Rep. 16, 1093–1098 (2006).

    CAS  PubMed  Google Scholar 

  72. Chalamalasetty, R. B., Hummer, S., Nigg, E. A. & Sillje, H. H. Influence of human Ect2 depletion and overexpression on cleavage furrow formation and abscission. J. Cell Sci. 119, 3008–3019 (2006).

    Article  CAS  PubMed  Google Scholar 

  73. Canevascini, S., Marti, M., Frohli, E. & Hajnal, A. The Caenorhabditis elegans homologue of the proto-oncogene ect-2 positively regulates RAS signalling during vulval development. EMBO Rep. 6, 1169–1175 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Justilien, V. et al. Ect2-dependent rRNA synthesis is required for KRAS-TRP53-driven lung adenocarcinoma. Cancer Cell 31, 256–269 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Gruneberg, U., Neef, R., Honda, R., Nigg, E. A. & Barr, F. A. Relocation of Aurora B from centromeres to the central spindle at the metaphase to anaphase transition requires MKlp2. J. Cell Biol. 166, 167–172 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Mollinari, C. et al. PRC1 is a microtubule binding and bundling protein essential to maintain the mitotic spindle midzone. J. Cell Biol. 157, 1175–1186 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. 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).

    Article  CAS  PubMed  Google Scholar 

  78. Li, J., Dallmayer, M., Kirchner, T., Musa, J. & Grunewald, T. G. P. PRC1: linking cytokinesis, chromosomal instability, and cancer evolution. Trends Cancer 4, 59–73 (2018).

    Article  PubMed  Google Scholar 

  79. Chen, J. et al. The microtubule-associated protein PRC1 promotes early recurrence of hepatocellular carcinoma in association with the Wnt/beta-catenin signalling pathway. Gut 65, 1522–1534 (2016).

    Article  CAS  PubMed  Google Scholar 

  80. Li, C., Lin, M. & Liu, J. Identification of PRC1 as the p53 target gene uncovers a novel function of p53 in the regulation of cytokinesis. Oncogene 23, 9336–9347 (2004).

    Article  CAS  PubMed  Google Scholar 

  81. Tarapore, P. & Fukasawa, K. Loss of p53 and centrosome hyperamplification. Oncogene 21, 6234–6240 (2002).

    Article  CAS  PubMed  Google Scholar 

  82. Zhan, P. et al. PRC1 contributes to tumorigenesis of lung adenocarcinoma in association with the Wnt/beta-catenin signaling pathway. Mol. Cancer 16, 108 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Claerhout, S. et al. Gene expression signature analysis identifies vorinostat as a candidate therapy for gastric cancer. PLOS ONE 6, e24662 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Ho, J. R. et al. Deregulation of Rab and Rab effector genes in bladder cancer. PLOS ONE 7, e39469 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Imai, K. et al. Identification of HLA-A2-restricted CTL epitopes of a novel tumour-associated antigen, KIF20A, overexpressed in pancreatic cancer. Br. J. Cancer 104, 300–307 (2011).

    Article  CAS  PubMed  Google Scholar 

  86. Tomita, Y. et al. Identification of promiscuous KIF20A long peptides bearing both CD4+ and CD8+ T cell epitopes: KIF20A-specific CD4+ T cell immunity in patients with malignant tumor. Clin. Cancer Res. 19, 4508–4520 (2013).

    Article  CAS  PubMed  Google Scholar 

  87. Gasnereau, I. et al. KIF20A mRNA and its product MKlp2 are increased during hepatocyte proliferation and hepatocarcinogenesis. Am. J. Pathol. 180, 131–140 (2012).

    Article  CAS  PubMed  Google Scholar 

  88. Jiang, W. et al. PRC1: a human mitotic spindle-associated CDK substrate protein required for cytokinesis. Mol. Cell 2, 877–885 (1998).

    Article  CAS  PubMed  Google Scholar 

  89. Liot, C. et al. APC(cdh1) mediates degradation of the oncogenic Rho-GEF Ect2 after mitosis. PLOS ONE 6, e23676 (2011).

    Google Scholar 

  90. Lind, G. E. et al. SPG20, a novel biomarker for early detection of colorectal cancer, encodes a regulator of cytokinesis. Oncogene 30, 3967–3978 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Renvoise, B. et al. SPG20 protein spartin is recruited to midbodies by ESCRT-III protein Ist1 and participates in cytokinesis. Mol. Biol. Cell 21, 3293–3303 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Renvoise, B., Stadler, J., Singh, R., Bakowska, J. C. & Blackstone, C. Spg20−/− mice reveal multimodal functions for Troyer syndrome protein spartin in lipid droplet maintenance, cytokinesis and BMP signaling. Hum. Mol. Genet. 21, 3604–3618 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Palomero, T. et al. Recurrent mutations in epigenetic regulators, RHOA and FYN kinase in peripheral T cell lymphomas. Nat. Genet. 46, 166–170 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Sakata-Yanagimoto, M. et al. Somatic RHOA mutation in angioimmunoblastic T cell lymphoma. Nat. Genet. 46, 171–175 (2014).

    Article  CAS  PubMed  Google Scholar 

  95. Yoo, H. Y. et al. A recurrent inactivating mutation in RHOA GTPase in angioimmunoblastic T cell lymphoma. Nat. Genet. 46, 371–375 (2014).

    Article  CAS  PubMed  Google Scholar 

  96. Manso, R. et al. The RHOA G17V gene mutation occurs frequently in peripheral T cell lymphoma and is associated with a characteristic molecular signature. Blood 123, 2893–2894 (2014).

    Article  CAS  PubMed  Google Scholar 

  97. Cancer Genome Atlas Research Network. Comprehensive molecular characterization of gastric adenocarcinoma. Nature 513, 202–209 (2014).

    Article  CAS  Google Scholar 

  98. Kakiuchi, M. et al. Recurrent gain-of-function mutations of RHOA in diffuse-type gastric carcinoma. Nat. Genet. 46, 583–587 (2014).

    Article  CAS  PubMed  Google Scholar 

  99. Wang, K. et al. Whole-genome sequencing and comprehensive molecular profiling identify new driver mutations in gastric cancer. Nat. Genet. 46, 573–582 (2014).

    Article  CAS  PubMed  Google Scholar 

  100. Rohde, M. et al. Recurrent RHOA mutations in pediatric Burkitt lymphoma treated according to the NHL-BFM protocols. Genes Chromosomes Cancer 53, 911–916 (2014).

    Article  CAS  PubMed  Google Scholar 

  101. Kataoka, K. & Ogawa, S. Variegated RHOA mutations in human cancers. Exp. Hematol. 44, 1123–1129 (2016).

    Article  CAS  PubMed  Google Scholar 

  102. Zhou, J., Hayakawa, Y., Wang, T. C. & Bass, A. J. RhoA mutations identified in diffuse gastric cancer. Cancer Cell 26, 9–11 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Sahai, E. & Marshall, C. J. RHO-GTPases and cancer. Nat. Rev. Cancer 2, 133–142 (2002).

    Article  PubMed  Google Scholar 

  104. Vitale, I., Galluzzi, L., Castedo, M. & Kroemer, G. Mitotic catastrophe: a mechanism for avoiding genomic instability. Nat. Rev. Mol. Cell Biol. 12, 385–392 (2011).

    Article  CAS  PubMed  Google Scholar 

  105. Gascoigne, K. E. & Taylor, S. S. Cancer cells display profound intra- and interline variation following prolonged exposure to antimitotic drugs. Cancer Cell 14, 111–122 (2008). This paper demonstrates that a mitotic delay induced by spindle poisons either results in mitotic slippage or mitotic cell death. The choice between these two different cell fates, one of which produces a genome-doubling event, is controlled by two competing pathways.

    Article  CAS  PubMed  Google Scholar 

  106. Brito, D. A. & Rieder, C. L. The ability to survive mitosis in the presence of microtubule poisons differs significantly between human nontransformed (RPE-1) and cancer (U2OS, HeLa) cells. Cell. Motil. Cytoskeleton 66, 437–447 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Orth, J. D. et al. Quantitative live imaging of cancer and normal cells treated with kinesin-5 inhibitors indicates significant differences in phenotypic responses and cell fate. Mol. Cancer Ther. 7, 3480–3489 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Shi, J., Orth, J. D. & Mitchison, T. Cell type variation in responses to antimitotic drugs that target microtubules and kinesin-5. Cancer Res. 68, 3269–3276 (2008).

    Article  CAS  PubMed  Google Scholar 

  109. Brito, D. A., Yang, Z. & Rieder, C. L. Microtubules do not promote mitotic slippage when the spindle assembly checkpoint cannot be satisfied. J. Cell Biol. 182, 623–629 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Brito, D. A. & Rieder, C. L. Mitotic checkpoint slippage in humans occurs via cyclin B destruction in the presence of an active checkpoint. Curr. Biol. 16, 1194–1200 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Gascoigne, K. E. & Taylor, S. S. How do anti-mitotic drugs kill cancer cells? J. Cell Sci. 122, 2579–2585 (2009).

    Article  CAS  PubMed  Google Scholar 

  112. Huang, H. C., Shi, J., Orth, J. D. & Mitchison, T. J. Evidence that mitotic exit is a better cancer therapeutic target than spindle assembly. Cancer Cell 16, 347–358 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Lehman, N. L., Verschuren, E. W., Hsu, J. Y., Cherry, A. M. & Jackson, P. K. Overexpression of the anaphase promoting complex/cyclosome inhibitor Emi1 leads to tetraploidy and genomic instability of p53-deficient cells. Cell Cycle 5, 1569–1573 (2006).

    Article  CAS  PubMed  Google Scholar 

  114. Margottin-Goguet, F. et al. Prophase destruction of Emi1 by the SCF(betaTrCP/Slimb) ubiquitin ligase activates the anaphase promoting complex to allow progression beyond prometaphase. Dev. Cell 4, 813–826 (2003).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  117. Hsu, J. Y., Reimann, J. D., Sorensen, C. S., Lukas, J. & Jackson, P. K. E2F-dependent accumulation of hEmi1 regulates S phase entry by inhibiting APC(Cdh1). Nat. Cell Biol. 4, 358–366 (2002).

    Article  CAS  PubMed  Google Scholar 

  118. Gorbsky, G. J. Cohesion fatigue. Curr. Biol. 23, R986–R988 (2013).

    Article  CAS  PubMed  Google Scholar 

  119. Daum, J. R. et al. Cohesion fatigue induces chromatid separation in cells delayed at metaphase. Curr. Biol. 21, 1018–1024 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Hengeveld, R. C. C., Vromans, M. J. M., Vleugel, M., Hadders, M. A. & Lens, S. M. A. Inner centromere localization of the CPC maintains centromere cohesion and allows mitotic checkpoint silencing. Nat. Commun. 8, 15542 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Zhou, L. et al. The N-terminal non-kinase-domain-mediated binding of haspin to Pds5B protects centromeric cohesion in mitosis. Curr. Biol. 27, 992–1004 (2017).

    Article  CAS  PubMed  Google Scholar 

  122. Sapkota, H., Wasiak, E., Daum, J. R. & Gorbsky, G. J. Multiple determinants and consequences of cohesion fatigue in mammalian cells. Mol. Biol. Cell 29, 1811–1824 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Kim, J. S. et al. Intact cohesion, anaphase, and chromosome segregation in human cells harboring tumor-derived mutations in STAG2. PLOS Genet. 12, e1005865 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  124. de Lange, J. et al. Defective sister chromatid cohesion is synthetically lethal with impaired APC/C function. Nat. Commun. 6, 8399 (2015).

    Article  PubMed  CAS  Google Scholar 

  125. Boveri, T. Zur Frage der Entstehung maligner Tumoren (G. Fischer, 1914). This paper is a must-read classic on the earliest observations of chromosome segregation errors and their consequences.

  126. Davoli, T. & de Lange, T. The causes and consequences of polyploidy in normal development and cancer. Annu. Rev. Cell Dev. Biol. 27, 585–610 (2011).

    Article  CAS  PubMed  Google Scholar 

  127. Dewhurst, S. M. et al. Tolerance of whole-genome doubling propagates chromosomal instability and accelerates cancer genome evolution. Cancer Discov. 4, 175–185 (2014). This is a landmark paper on the effect of genome-doubling events on cancer evolution.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Lv, L. et al. Tetraploid cells from cytokinesis failure induce aneuploidy and spontaneous transformation of mouse ovarian surface epithelial cells. Cell Cycle 11, 2864–2875 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Borel, F., Lohez, O. D., Lacroix, F. B. & Margolis, R. L. Multiple centrosomes arise from tetraploidy checkpoint failure and mitotic centrosome clusters in p53 and RB pocket protein-compromised cells. Proc. Natl Acad. Sci. USA 99, 9819–9824 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Kwon, M. et al. Mechanisms to suppress multipolar divisions in cancer cells with extra centrosomes. Genes Dev. 22, 2189–2203 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Quintyne, N. J., Reing, J. E., Hoffelder, D. R., Gollin, S. M. & Saunders, W. S. Spindle multipolarity is prevented by centrosomal clustering. Science 307, 127–129 (2005). This paper provides a suitable explanation for the fact that tumour cells can tolerate centrosome amplifications.

    Article  CAS  PubMed  Google Scholar 

  133. Godinho, S. A. & Pellman, D. Causes and consequences of centrosome abnormalities in cancer. Phil. Trans. R. Soc. B 369, 20130467 (2014).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  134. Shoshani, O. et al. Polyploidization of murine mesenchymal cells is associated with suppression of the long noncoding RNA H19 and reduced tumorigenicity. Cancer Res. 72, 6403–6413 (2012).

    Article  CAS  PubMed  Google Scholar 

  135. Levine, M. S. et al. Centrosome amplification is sufficient to promote spontaneous tumorigenesis in mammals. Dev. Cell 40, 313–322 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Basto, R. et al. Centrosome amplification can initiate tumorigenesis in flies. Cell 133, 1032–1042 (2008). This paper provides the first direct evidence that centrosome amplification per se can promote tumorigenesis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Sercin, O. et al. Transient PLK4 overexpression accelerates tumorigenesis in p53-deficient epidermis. Nat. Cell Biol. 18, 100–110 (2016).

    Article  CAS  PubMed  Google Scholar 

  138. Vitre, B. et al. Chronic centrosome amplification without tumorigenesis. Proc. Natl Acad. Sci. USA 112, E6321–E6330 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Janssen, A., van der Burg, M., Szuhai, K., Kops, G. J. & Medema, R. H. Chromosome segregation errors as a cause of DNA damage and structural chromosome aberrations. Science 333, 1895–1898 (2011). This paper describes how missegregating chromosomes can break during cytokinesis, giving rise to non-reciprocal or unbalanced translocations.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  141. Aplan, P. D. Causes of oncogenic chromosomal translocation. Trends Genet. 22, 46–55 (2006).

    Article  CAS  PubMed  Google Scholar 

  142. Crasta, K. et al. DNA breaks and chromosome pulverization from errors in mitosis. Nature 482, 53–58 (2012). This paper describes how lagging chromosomes that end up in micronuclei can shatter, possibly giving rise to dramatic chromosome rearrangements.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Liu, S. et al. Nuclear envelope assembly defects link mitotic errors to chromothripsis. Nature 561, 551–555 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Ly, P. et al. Selective Y centromere inactivation triggers chromosome shattering in micronuclei and repair by non-homologous end joining. Nat. Cell Biol. 19, 68–75 (2017).

    Article  CAS  PubMed  Google Scholar 

  145. Hatch, E. M., Fischer, A. H., Deerinck, T. J. & Hetzer, M. W. Catastrophic nuclear envelope collapse in cancer cell micronuclei. Cell 154, 47–60 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Zhang, C. Z. et al. Chromothripsis from DNA damage in micronuclei. Nature 522, 179–184 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Van de Peer, Y., Mizrachi, E. & Marchal, K. The evolutionary significance of polyploidy. Nat. Rev. Genet. 18, 411–424 (2017).

    Article  PubMed  CAS  Google Scholar 

  148. Gerstein, A. C. et al. Polyploid titan cells produce haploid and aneuploid progeny to promote stress adaptation. mBio 6, e01340–15 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Selmecki, A. M. et al. Polyploidy can drive rapid adaptation in yeast. Nature 519, 349–352 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Carter, S. B. Effects of cytochalasins on mammalian cells. Nature 213, 261–264 (1967).

    Article  CAS  PubMed  Google Scholar 

  152. Wright, W. E. & Hayflick, L. Formation of anucleate and multinucleate cells in normal and SV 40 transformed WI-38 by cytochalasin B. Exp. Cell Res. 74, 187–194 (1972).

    Article  CAS  PubMed  Google Scholar 

  153. Cross, S. M. et al. A p53-dependent mouse spindle checkpoint. Science 267, 1353–1356 (1995).

    Article  CAS  PubMed  Google Scholar 

  154. Uetake, Y. & Sluder, G. Cell cycle progression after cleavage failure: mammalian somatic cells do not possess a “tetraploidy checkpoint”. J. Cell Biol. 165, 609–615 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Coelho, P. A. et al. Over-expression of Plk4 induces centrosome amplification, loss of primary cilia and associated tissue hyperplasia in the mouse. Open Biol. 5, 150209 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  156. Kulukian, A. et al. Epidermal development, growth control, and homeostasis in the face of centrosome amplification. Proc. Natl Acad. Sci. USA 112, E6311–E6320 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Laffin, J., Fogleman, D. & Lehman, J. M. Correlation of DNA content, p53, T antigen, and V antigen in simian virus 40-infected human diploid cells. Cytometry 10, 205–213 (1989).

    Article  CAS  PubMed  Google Scholar 

  158. Schwartz, D., Goldfinger, N. & Rotter, V. Expression of p53 protein in spermatogenesis is confined to the tetraploid pachytene primary spermatocytes. Oncogene 8, 1487–1494 (1993).

    CAS  PubMed  Google Scholar 

  159. Lanni, J. S. & Jacks, T. Characterization of the p53-dependent postmitotic checkpoint following spindle disruption. Mol. Cell. Biol. 18, 1055–1064 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Andreassen, P. R., Lohez, O. D., Lacroix, F. B. & Margolis, R. L. Tetraploid state induces p53-dependent arrest of nontransformed mammalian cells in G1. Mol. Biol. Cell 12, 1315–1328 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Kuffer, C., Kuznetsova, A. Y. & Storchova, Z. Abnormal mitosis triggers p53-dependent cell cycle arrest in human tetraploid cells. Chromosoma 122, 305–318 (2013).

    Article  CAS  PubMed  Google Scholar 

  162. Hinchcliffe, E. H., Miller, F. J., Cham, M., Khodjakov, A. & Sluder, G. Requirement of a centrosomal activity for cell cycle progression through G1 into S phase. Science 291, 1547–1550 (2001).

    Article  CAS  PubMed  Google Scholar 

  163. Khodjakov, A. & Rieder, C. L. Centrosomes enhance the fidelity of cytokinesis in vertebrates and are required for cell cycle progression. J. Cell Biol. 153, 237–242 (2001). This paper nicely describes how centrosome defects affect the fidelity of cytokinesis and provides the first evidence that a human cell that is generated without a centrosome arrests in G1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Gromley, A. et al. A novel human protein of the maternal centriole is required for the final stages of cytokinesis and entry into S phase. J. Cell Biol. 161, 535–545 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Mikule, K. et al. Loss of centrosome integrity induces p38-p53-p21-dependent G1-S arrest. Nat. Cell Biol. 9, 160–170 (2007).

    Article  CAS  PubMed  Google Scholar 

  166. Fong, C. S. et al. 53BP1 and USP28 mediate p53-dependent cell cycle arrest in response to centrosome loss and prolonged mitosis. eLife 5, e16270 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  167. Lambrus, B. G. et al. A USP28-53BP1-p53-p21 signaling axis arrests growth after centrosome loss or prolonged mitosis. J. Cell Biol. 214, 143–153 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Meitinger, F. et al. 53BP1 and USP28 mediate p53 activation and G1 arrest after centrosome loss or extended mitotic duration. J. Cell Biol. 214, 155–166 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Aylon, Y. et al. A positive feedback loop between the p53 and Lats2 tumor suppressors prevents tetraploidization. Genes Dev. 20, 2687–2700 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. McPherson, J. P. et al. Lats2/Kpm is required for embryonic development, proliferation control and genomic integrity. EMBO J. 23, 3677–3688 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Ganem, N. J. et al. Cytokinesis failure triggers hippo tumor suppressor pathway activation. Cell 158, 833–848 (2014). This paper provides the first description of Hippo pathway activation in response to cytokinesis failure.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Holland, A. J. et al. The autoregulated instability of Polo-like kinase 4 limits centrosome duplication to once per cell cycle. Genes Dev. 26, 2684–2689 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Zhang, S. et al. Hippo signaling suppresses cell ploidy and tumorigenesis through Skp2. Cancer Cell 31, 669–684 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Waterman-Storer, C. M., Worthylake, R. A., Liu, B. P., Burridge, K. & Salmon, E. D. Microtubule growth activates Rac1 to promote lamellipodial protrusion in fibroblasts. Nat. Cell Biol. 1, 45–50 (1999).

    Article  CAS  PubMed  Google Scholar 

  175. Godinho, S. A. et al. Oncogene-like induction of cellular invasion from centrosome amplification. Nature 510, 167–171 (2014). This study provides direct evidence that centrosome amplification per se is sufficient to introduce properties of oncogenic transformation into an otherwise non-transformed cell.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Yu, F. X. et al. Regulation of the Hippo-YAP pathway by G-protein-coupled receptor signaling. Cell 150, 780–791 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Brown, C. R., Doxsey, S. J., White, E. & Welch, W. J. Both viral (adenovirus E1B) and cellular (hsp 70, p53) components interact with centrosomes. J. Cell. Physiol. 160, 47–60 (1994).

    Article  CAS  PubMed  Google Scholar 

  178. Ciciarello, M. et al. p53 displacement from centrosomes and p53-mediated G1 arrest following transient inhibition of the mitotic spindle. J. Biol. Chem. 276, 19205–19213 (2001).

    Article  CAS  PubMed  Google Scholar 

  179. Morris, V. B., Brammall, J., Noble, J. & Reddel, R. p53 localizes to the centrosomes and spindles of mitotic cells in the embryonic chick epiblast, human cell lines, and a human primary culture: an immunofluorescence study. Exp. Cell Res. 256, 122–130 (2000).

    Article  CAS  PubMed  Google Scholar 

  180. Fava, L. L. et al. The PIDDosome activates p53 in response to supernumerary centrosomes. Genes Dev. 31, 34–45 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Tinel, A. & Tschopp, J. The PIDDosome, a protein complex implicated in activation of caspase-2 in response to genotoxic stress. Science 304, 843–846 (2004).

    Article  CAS  PubMed  Google Scholar 

  182. Jahn, S. C. et al. Constitutive Cdk2 activity promotes aneuploidy while altering the spindle assembly and tetraploidy checkpoints. J. Cell Sci. 126, 1207–1217 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Lohez, O. D., Reynaud, C., Borel, F., Andreassen, P. R. & Margolis, R. L. Arrest of mammalian fibroblasts in G1 in response to actin inhibition is dependent on retinoblastoma pocket proteins but not on p53. J. Cell Biol. 161, 67–77 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Crockford, A. et al. Cyclin D mediates tolerance of genome-doubling in cancers with functional p53. Ann. Oncol. 28, 149–156 (2017).

    CAS  PubMed  Google Scholar 

  185. Potapova, T. A., Seidel, C. W., Box, A. C., Rancati, G. & Li, R. Transcriptome analysis of tetraploid cells identifies cyclin D2 as a facilitator of adaptation to genome doubling in the presence of p53. Mol. Biol. Cell 27, 3065–3084 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Roy, A. et al. Uncoupling of the Hippo and Rho pathways allows megakaryocytes to escape the tetraploid checkpoint. Haematologica 101, 1469–1478 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Rhys, A. D. et al. Loss of E-cadherin provides tolerance to centrosome amplification in epithelial cancer cells. J. Cell Biol. 217, 195–209 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Tanaka, H. et al. Cytokinetic failure-induced tetraploidy develops into aneuploidy, triggering skin aging in phosphovimentin-deficient mice. J. Biol. Chem. 290, 12984–12998 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. De Santis Puzzonia, M., Gonzalez, L., Ascenzi, S., Cundari, E. & Degrassi, F. Tetraploid cells produced by absence of substrate adhesion during cytokinesis are limited in their proliferation and enter senescence after DNA replication. Cell Cycle 15, 274–282 (2016).

    Article  PubMed  CAS  Google Scholar 

  190. Sadaie, M. et al. Cell-based screen for altered nuclear phenotypes reveals senescence progression in polyploid cells after Aurora kinase B inhibition. Mol. Biol. Cell 26, 2971–2985 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Panopoulos, A. et al. Failure of cell cleavage induces senescence in tetraploid primary cells. Mol. Biol. Cell 25, 3105–3118 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  192. Vitale, I., Manic, G., Castedo, M. & Kroemer, G. Caspase 2 in mitotic catastrophe: the terminator of aneuploid and tetraploid cells. Mol. Cell. Oncol. 4, e1299274 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Pedersen, R. S. et al. Profiling DNA damage response following mitotic perturbations. Nat. Commun. 7, 13887 (2016).

    Article  CAS  Google Scholar 

  195. 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).

    Article  CAS  PubMed  Google Scholar 

  196. Ablasser, A. et al. cGAS produces a 2′-5′-linked cyclic dinucleotide second messenger that activates STING. Nature 498, 380–384 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Diner, E. J. et al. The innate immune DNA sensor cGAS produces a noncanonical cyclic dinucleotide that activates human STING. Cell Rep. 3, 1355–1361 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Gao, P. et al. Cyclic [G(2′,5′)pA(3′,5′)p] is the metazoan second messenger produced by DNA-activated cyclic GMP-AMP synthase. Cell 153, 1094–1107 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Zhang, X. et al. Cyclic GMP-AMP containing mixed phosphodiester linkages is an endogenous high-affinity ligand for STING. Mol. Cell 51, 226–235 (2013). References 195–199 describe the identification of cGAS as a cytosolic DNA sensor that can promote activation of the innate immune response.

    Article  CAS  PubMed  Google Scholar 

  200. Li, T. & Chen, Z. J. The cGAS-cGAMP-STING pathway connects DNA damage to inflammation, senescence, and cancer. J. Exp. Med. 215, 1287–1299 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. de Oliveira Mann, C. C. & Kranzusch, P. J. cGAS conducts micronuclei DNA surveillance. Trends Cell Biol. 27, 697–698 (2017).

    Article  PubMed  CAS  Google Scholar 

  202. Harding, S. M. et al. Mitotic progression following DNA damage enables pattern recognition within micronuclei. Nature 548, 466–470 (2017). This paper demonstrates that cGAS is activated by damaged DNA in micronuclei. It also contains data showing that the activation of cGAS in this way can play a role in the abscopal effect (radiotherapy-induced regression of tumours that lie outside of the radiation field).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Mackenzie, K. J. et al. cGAS surveillance of micronuclei links genome instability to innate immunity. Nature 548, 461–465 (2017). This paper also demonstrates that cGAS is activated by damaged DNA in micronuclei, as well as by DNA in micronuclei formed from lagging chromosomes. It contains data showing that activation of cGAS is associated with rupture of the micronuclei.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. 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). This paper demonstrates that the acquisition of an aneuploid karyotype triggers activation of an innate immune response.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Bakhoum, S. F. et al. Chromosomal instability drives metastasis through a cytosolic DNA response. Nature 553, 467–472 (2018). This paper provides evidence that activation of the cGAS–STING pathway, induced by chromosome segregation errors, can promote cancer cell invasion and metastasis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. 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). This study analyses 12 different human cancer types and demonstrates that highly aneuploid tumours display a reduction in infiltrating cytotoxic T cells, implying that aneuploidy does not stimulate an antitumour immune response.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  207. McKenzie, C. & D’Avino, P. P. Investigating cytokinesis failure as a strategy in cancer therapy. Oncotarget 7, 87323–87341 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  208. Wutz, A. Haploid animal cells. Development 141, 1423–1426 (2014).

    Article  CAS  PubMed  Google Scholar 

  209. Pera, F. & Rainer, B. Studies of multipolar mitoses in euploid tissue cultures. I. Somatic reduction to exactly haploid and triploid chromosome sets. Chromosoma 42, 71–86 (1973).

    Article  CAS  PubMed  Google Scholar 

  210. Carlton, J. G., Caballe, A., Agromayor, M., Kloc, M. & Martin-Serrano, J. ESCRT-III governs the Aurora B-mediated abscission checkpoint through CHMP4C. Science 336, 220–225 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Cuylen, S., Metz, J., Hruby, A. & Haering, C. H. Entrapment of chromosomes by condensin rings prevents their breakage during cytokinesis. Dev. Cell 27, 469–478 (2013).

    Article  CAS  PubMed  Google Scholar 

  212. Dandoulaki, M., Petsalaki, E., Sumpton, D., Zanivan, S. & Zachos, G. Src activation by Chk1 promotes actin patch formation and prevents chromatin bridge breakage in cytokinesis. J. Cell Biol. 217, 3071–3089 (2018).

  213. Thompson, S. L. & Compton, D. A. Chromosome missegregation in human cells arises through specific types of kinetochore-microtubule attachment errors. Proc. Natl Acad. Sci. USA 108, 17974–17978 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. van Heesbeen, R. G., Tanenbaum, M. E. & Medema, R. H. Balanced activity of three mitotic motors is required for bipolar spindle assembly and chromosome segregation. Cell Rep. 8, 948–956 (2014).

    Article  PubMed  CAS  Google Scholar 

  215. Lingle, W. L., Lukasiewicz, K. & Salisbury, J. L. Deregulation of the centrosome cycle and the origin of chromosomal instability in cancer. Adv. Exp. Med. Biol. 570, 393–421 (2005).

    Article  CAS  PubMed  Google Scholar 

  216. Maiato, H. & Logarinho, E. Mitotic spindle multipolarity without centrosome amplification. Nat. Cell Biol. 16, 386–394 (2014).

    Article  CAS  PubMed  Google Scholar 

  217. Walczak, C. E. & Heald, R. Mechanisms of mitotic spindle assembly and function. Int. Rev. Cytol. 265, 111–158 (2008).

    Article  CAS  PubMed  Google Scholar 

  218. Ertych, N. et al. Increased microtubule assembly rates influence chromosomal instability in colorectal cancer cells. Nat. Cell Biol. 16, 779–791 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. Meraldi, P., Honda, R. & Nigg, E. A. Aurora-A overexpression reveals tetraploidization as a major route to centrosome amplification in p53−/− cells. EMBO J. 21, 483–492 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  220. Stimpson, K. M., Matheny, J. E. & Sullivan, B. A. Dicentric chromosomes: unique models to study centromere function and inactivation. Chromosome Res. 20, 595–605 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  221. Artandi, S. E. et al. Telomere dysfunction promotes non-reciprocal translocations and epithelial cancers in mice. Nature 406, 641–645 (2000).

    Article  CAS  PubMed  Google Scholar 

  222. van Steensel, B., Smogorzewska, A. & de Lange, T. TRF2 protects human telomeres from end-to-end fusions. Cell 92, 401–413 (1998).

    Article  PubMed  Google Scholar 

  223. Mankouri, H. W., Huttner, D. & Hickson, I. D. How unfinished business from S-phase affects mitosis and beyond. EMBO J. 32, 2661–2671 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  224. Chan, K. L., Palmai-Pallag, T., Ying, S. & Hickson, I. D. Replication stress induces sister-chromatid bridging at fragile site loci in mitosis. Nat. Cell Biol. 11, 753–760 (2009).

    Article  CAS  PubMed  Google Scholar 

  225. Naim, V. & Rosselli, F. The FANC pathway and BLM collaborate during mitosis to prevent micro-nucleation and chromosome abnormalities. Nat. Cell Biol. 11, 761–768 (2009).

    Article  CAS  PubMed  Google Scholar 

  226. Ying, S. et al. MUS81 promotes common fragile site expression. Nat. Cell Biol. 15, 1001–1007 (2013).

    Article  CAS  PubMed  Google Scholar 

  227. Sundin, O. & Varshavsky, A. Terminal stages of SV40 DNA replication proceed via multiply intertwined catenated dimers. Cell 21, 103–114 (1980).

    Article  CAS  PubMed  Google Scholar 

  228. Spence, J. M. et al. Depletion of topoisomerase IIalpha leads to shortening of the metaphase interkinetochore distance and abnormal persistence of PICH-coated anaphase threads. J. Cell Sci. 120, 3952–3964 (2007).

    Article  CAS  PubMed  Google Scholar 

  229. Baumann, C., Korner, R., Hofmann, K. & Nigg, E. A. PICH, a centromere-associated SNF2 family ATPase, is regulated by Plk1 and required for the spindle checkpoint. Cell 128, 101–114 (2007).

    Article  CAS  PubMed  Google Scholar 

  230. Hengeveld, R. C. et al. Rif1 is required for resolution of ultrafine DNA bridges in anaphase to ensure genomic stability. Dev. Cell 34, 466–474 (2015).

    Article  CAS  PubMed  Google Scholar 

  231. Usui, T. et al. Uncoupled cell cycle without mitosis induced by a protein kinase inhibitor, K-252a. J. Cell Biol. 115, 1275–1282 (1991).

    Article  CAS  PubMed  Google Scholar 

  232. Dahmann, C., Diffley, J. F. & Nasmyth, K. A. S-phase-promoting cyclin-dependent kinases prevent re-replication by inhibiting the transition of replication origins to a pre-replicative state. Curr. Biol. 5, 1257–1269 (1995).

    Article  CAS  PubMed  Google Scholar 

  233. Bates, S., Ryan, K. M., Phillips, A. C. & Vousden, K. H. Cell cycle arrest and DNA endoreduplication following p21Waf1/Cip1 expression. Oncogene 17, 1691–1703 (1998).

    Article  CAS  PubMed  Google Scholar 

  234. Niculescu, A. B. III et al. Effects of p21(Cip1/Waf1) at both the G1/S and the G2/M cell cycle transitions: pRb is a critical determinant in blocking DNA replication and in preventing endoreduplication. Mol. Cell. Biol. 18, 629–643 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  235. Davoli, T., Denchi, E. L. & de Lange, T. Persistent telomere damage induces bypass of mitosis and tetraploidy. Cell 141, 81–93 (2010). This paper shows that telomere dysfunction readily induces tetraploidization by inducing a prolonged G2 arrest, from which cells escape by bypassing mitosis. This implies that genome-doubling events can also arise from (transient) telomere-specific defects.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  236. Bunz, F. et al. Requirement for p53 and p21 to sustain G2 arrest after DNA damage. Science 282, 1497–1501 (1998).

    Article  CAS  PubMed  Google Scholar 

  237. Waldman, T., Lengauer, C., Kinzler, K. W. & Vogelstein, B. Uncoupling of S phase and mitosis induced by anticancer agents in cells lacking p21. Nature 381, 713–716 (1996).

    Article  CAS  PubMed  Google Scholar 

  238. Chen, E. H., Grote, E., Mohler, W. & Vignery, A. Cell-cell fusion. FEBS Lett. 581, 2181–2193 (2007).

    Article  CAS  PubMed  Google Scholar 

  239. De Baetselier, P. et al. Nonmetastatic tumor cells acquire metastatic properties following somatic hybridization with normal cells. Cancer Metastasis Rev. 3, 5–24 (1984).

    Article  PubMed  Google Scholar 

  240. Duelli, D. & Lazebnik, Y. Cell fusion: a hidden enemy? Cancer Cell 3, 445–448 (2003).

    Article  CAS  PubMed  Google Scholar 

  241. Ogle, B. M., Cascalho, M. & Platt, J. L. Biological implications of cell fusion. Nat. Rev. Mol. Cell Biol. 6, 567–575 (2005).

    Article  CAS  PubMed  Google Scholar 

  242. Gao, P. & Zheng, J. Oncogenic virus-mediated cell fusion: new insights into initiation and progression of oncogenic viruses-related cancers. Cancer Lett. 303, 1–8 (2011).

    Article  CAS  PubMed  Google Scholar 

  243. Fededa, J. P. & Gerlich, D. W. Molecular control of animal cell cytokinesis. Nat. Cell Biol. 14, 440–447 (2012).

    Article  CAS  PubMed  Google Scholar 

  244. Glotzer, M. The 3Ms of central spindle assembly: microtubules, motors and MAPs. Nat. Rev. Mol. Cell Biol. 10, 9–20 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  245. Choudhary, A. et al. Interphase cytofission maintains genomic integrity of human cells after failed cytokinesis. Proc. Natl Acad. Sci. USA 110, 13026–13031 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors thank the reviewers for their constructive suggestions for improvement. The authors apologize to all of their colleagues whose work could not be cited in this Review because of space limitations. This work is part of Oncode Institute, which is partly financed by the Dutch Cancer Society.

Reviewer information

Nature Reviews Cancer thanks M. Burkard, A. Holland and the other anonymous reviewer for their contribution to the peer review of this work.

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Authors and Affiliations

  1. Oncode Institute, Utrecht, Netherlands

    Susanne M. A. Lens & René H. Medema

  2. Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands

    Susanne M. A. Lens

  3. Division of Cell Biology and Cancer Genomics Center, The Netherlands Cancer Institute, Amsterdam, Netherlands

    René H. Medema

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S.M.A.L. and R.H.M. contributed equally to writing the article and to review and editing of the manuscript before submission.

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Correspondence to Susanne M. A. Lens or René H. Medema.

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Related links

cBioPortal: http://www.cbioportal.org/

NCI Cancer Genome Anatomy Project: https://cgap.nci.nih.gov/Chromosomes/Mitelman

Supplementary information

Glossary

Ploidy

The number of chromosomes in the nucleus of a cell.

Tetraploid cell

A cell that has four copies of each chromosome (4N).

Aneuploid cells

Cells with an abnormal chromosome content (a number that deviates from a multiple of the haploid (N) set). It encompasses both numerical aneuploidies (gains and/or losses of whole chromosomes) and structural aneuploidies (gains or losses of chromosome segments, including imbalanced translocations).

Chromosomal instability

(CIN). An elevated frequency of chromosome segregation errors during mitosis.

Centrosomes

Organelles consisting of two centrioles and surrounding pericentriolar material that serves as the main microtubule-nucleating and organizing centre of mammalian cells.

Chromosomal passenger complex

(CPC). A protein complex consisting of the mitotic kinase Aurora B, and three non-enzymatic subunits: INCENP, borealin and survivin. It has a dynamic localization in the dividing cell, localizing to the inner centromere region in late prophase and (pro)metaphase, the central spindle and equatorial cortex in anaphase and the midbody in telophase. The complex is essential for the acquisition of proper chromosome–spindle connections and for proper execution of cytokinesis.

Buccal micronucleus cytome assay

A non-invasive assay using exfoliated buccal cells to quantify the mean frequencies of cells containing aberrant nuclei, such as micronuclei (pieces of DNA that reside outside of the nucleus caused by chromosome breakage or missegregation), binucleation and abnormal chromatin condensation.

Chromatin bridge

A DNA structure that is observed in anaphase when the centromeres of the two sister chromatids are pulled towards opposite spindle poles but the sisters remain connected through, for instance, telomere fusion or regions of incompletely replicated DNA.

Cohesion fatigue

Loss of sister chromatid cohesion before anaphase onset that can occur as a consequence of a prolonged metaphase arrest or as a consequence of defects in the machinery that controls timely establishment and loss of cohesin.

Sister chromatids

The two identical copies of a single replicated chromosome that are kept together by DNA catenation and the cohesin complex from S phase until anaphase.

Mutator phenotype

An increase in mutation rate in cancer cells.

Dicentric chromosomes

Abnormal chromosomes with two centromeres, which are usually formed through the fusion of two chromosome segments.

Centromeres

Specialized regions of the chromosome where the kinetochore is assembled, thereby directing the segregation of the chromosomes.

DNA catenanes

Structures generated from the intertwining of replicated sister strands, which occurs when two converging replication forks meet. DNA catenanes are a normal consequence of DNA replication and are resolved during mitosis.

Kinetochore

A multi-protein complex that assembles on centromeres and serves as the main microtubule binding site of the chromosome. It also acts as a signalling platform for the mitotic checkpoint, which is a surveillance mechanism that prevents anaphase onset until all chromosomes are properly connected to the mitotic spindle.

Non-reciprocal translocations

Transfer of a chromosomal fragment of one chromosome to another non-homologous chromosome.

Replication stress

The slowing or stalling of replication fork progression owing to replication barriers formed by difficult to replicate regions, shortage of ribonucleotides or collisions between active translation and replication.

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Lens, S.M.A., Medema, R.H. Cytokinesis defects and cancer. Nat Rev Cancer 19, 32–45 (2019). https://doi.org/10.1038/s41568-018-0084-6

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