Chromosome Mis-segregation Generates Cell-Cycle-Arrested Cells with Complex Karyotypes That Are Eliminated by the Immune System

Overview

Journal Dev Cell

Publisher Cell Press

Specialties Cell Biology
Reproductive Medicine

Date 2017 Jun 21

PMID 28633018

Citations 188

Authors

Stefano Santaguida

Amelia Richardson

Divya Ramalingam Iyer

Ons MSaad

Lauren Zasadil

Kristin A Knouse

Yao Liang Wong

Nicholas Rhind

Arshad Desai

Angelika Amon

Affiliations

Soon will be listed here.

Abstract

Aneuploidy, a state of karyotype imbalance, is a hallmark of cancer. Changes in chromosome copy number have been proposed to drive disease by modulating the dosage of cancer driver genes and by promoting cancer genome evolution. Given the potential of cells with abnormal karyotypes to become cancerous, do pathways that limit the prevalence of such cells exist? By investigating the immediate consequences of aneuploidy on cell physiology, we identified mechanisms that eliminate aneuploid cells. We find that chromosome mis-segregation leads to further genomic instability that ultimately causes cell-cycle arrest. We further show that cells with complex karyotypes exhibit features of senescence and produce pro-inflammatory signals that promote their clearance by the immune system. We propose that cells with abnormal karyotypes generate a signal for their own elimination that may serve as a means for cancer cell immunosurveillance.

Citing Articles

The Role of p53 Mutations in Early and Late Response to Mitotic Aberrations.

Hertel A, Storchova Z Biomolecules. 2025; 15(2).

PMID: 40001547 PMC: 11852650. DOI: 10.3390/biom15020244.

Proteogenomic analysis reveals adaptive strategies for alleviating the consequences of aneuploidy in cancer.

Bokenkamp J, Keuper K, Redel S, Barthel K, Johnson L, Becker A EMBO J. 2025; .

PMID: 39930267 DOI: 10.1038/s44318-025-00372-w.

Chromosome number alterations cause apoptosis and cellular hypertrophy in induced pluripotent stem cell models of embryonic epiblast cells.

Martis A, Soundararajan L, Shetty P, Moin S, Vanje T, Jai Sankar Y Biol Open. 2025; 14(1).

PMID: 39851179 PMC: 11789280. DOI: 10.1242/bio.061814.

Chromosome mis-segregation triggers cell cycle arrest through a mechanosensitive nuclear envelope checkpoint.

Herve S, Scelfo A, Bersano Marchisio G, Grison M, Vaidziulyte K, Dumont M Nat Cell Biol. 2025; 27(1):73-86.

PMID: 39779939 PMC: 11735390. DOI: 10.1038/s41556-024-01565-x.

Long noncoding RNA, is associated with aneuploidy and its magnitude of expression level is dependent on P53 status.

Malakar P Front Cell Dev Biol. 2025; 12:1410308.

PMID: 39763585 PMC: 11702365. DOI: 10.3389/fcell.2024.1410308.

References

Mayer T, Kapoor T, Haggarty S, King R, Schreiber S, Mitchison T . Small molecule inhibitor of mitotic spindle bipolarity identified in a phenotype-based screen. Science. 1999; 286(5441):971-4. DOI: 10.1126/science.286.5441.971. View

Kyriakis J, Avruch J . Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. Physiol Rev. 2001; 81(2):807-69. DOI: 10.1152/physrev.2001.81.2.807. View

Hassold T, Hunt P . To err (meiotically) is human: the genesis of human aneuploidy. Nat Rev Genet. 2001; 2(4):280-91. DOI: 10.1038/35066065. View

Baker D, Jeganathan K, Cameron J, Thompson M, Juneja S, Kopecka A . BubR1 insufficiency causes early onset of aging-associated phenotypes and infertility in mice. Nat Genet. 2004; 36(7):744-9. DOI: 10.1038/ng1382. View

Kops G, Weaver B, Cleveland D . On the road to cancer: aneuploidy and the mitotic checkpoint. Nat Rev Cancer. 2005; 5(10):773-85. DOI: 10.1038/nrc1714. View

Roper R, Reeves R . Understanding the basis for Down syndrome phenotypes. PLoS Genet. 2006; 2(3):e50. PMC: 1420680. DOI: 10.1371/journal.pgen.0020050. View

Niwa O, Tange Y, Kurabayashi A . Growth arrest and chromosome instability in aneuploid yeast. Yeast. 2006; 23(13):937-50. DOI: 10.1002/yea.1411. View

Torres E, Sokolsky T, Tucker C, Chan L, Boselli M, Dunham M . Effects of aneuploidy on cellular physiology and cell division in haploid yeast. Science. 2007; 317(5840):916-24. DOI: 10.1126/science.1142210. View

Hodgkin J . Karyotype, ploidy, and gene dosage. WormBook. 2007; :1-9. PMC: 4781021. DOI: 10.1895/wormbook.1.3.1. View

10.

Walther A, Houlston R, Tomlinson I . Association between chromosomal instability and prognosis in colorectal cancer: a meta-analysis. Gut. 2008; 57(7):941-50. DOI: 10.1136/gut.2007.135004. View

11.

Krizhanovsky V, Yon M, Dickins R, Hearn S, Simon J, Miething C . Senescence of activated stellate cells limits liver fibrosis. Cell. 2008; 134(4):657-67. PMC: 3073300. DOI: 10.1016/j.cell.2008.06.049. View

12.

Williams B, Prabhu V, Hunter K, Glazier C, Whittaker C, Housman D . Aneuploidy affects proliferation and spontaneous immortalization in mammalian cells. Science. 2008; 322(5902):703-9. PMC: 2701511. DOI: 10.1126/science.1160058. View

13.

ODriscoll M . Haploinsufficiency of DNA Damage Response Genes and their Potential Influence in Human Genomic Disorders. Curr Genomics. 2009; 9(3):137-46. PMC: 2679649. DOI: 10.2174/138920208784340795. View

14.

Holland A, Cleveland D . Boveri revisited: chromosomal instability, aneuploidy and tumorigenesis. Nat Rev Mol Cell Biol. 2009; 10(7):478-87. PMC: 3154738. DOI: 10.1038/nrm2718. View

15.

Raulet D, Guerra N . Oncogenic stress sensed by the immune system: role of natural killer cell receptors. Nat Rev Immunol. 2009; 9(8):568-80. PMC: 3017432. DOI: 10.1038/nri2604. View

16.

Heilig C, Loffler H, Mahlknecht U, Janssen J, Ho A, Jauch A . Chromosomal instability correlates with poor outcome in patients with myelodysplastic syndromes irrespectively of the cytogenetic risk group. J Cell Mol Med. 2009; 14(4):895-902. PMC: 3823121. DOI: 10.1111/j.1582-4934.2009.00905.x. View

17.

Thompson S, Compton D . Proliferation of aneuploid human cells is limited by a p53-dependent mechanism. J Cell Biol. 2010; 188(3):369-81. PMC: 2819684. DOI: 10.1083/jcb.200905057. View

18.

Freund A, Orjalo A, Desprez P, Campisi J . Inflammatory networks during cellular senescence: causes and consequences. Trends Mol Med. 2010; 16(5):238-46. PMC: 2879478. DOI: 10.1016/j.molmed.2010.03.003. View

19.

Hewitt L, Tighe A, Santaguida S, White A, Jones C, Musacchio A . Sustained Mps1 activity is required in mitosis to recruit O-Mad2 to the Mad1-C-Mad2 core complex. J Cell Biol. 2010; 190(1):25-34. PMC: 2911659. DOI: 10.1083/jcb.201002133. View

20.

Santaguida S, Tighe A, DAlise A, Taylor S, Musacchio A . Dissecting the role of MPS1 in chromosome biorientation and the spindle checkpoint through the small molecule inhibitor reversine. J Cell Biol. 2010; 190(1):73-87. PMC: 2911657. DOI: 10.1083/jcb.201001036. View