Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
ReviewMerotelic kinetochore orientation, aneuploidy, and cancer
Section snippets
Aneuploidy in humans
Maintenance of a correct chromosome number is necessary for the development and survival of an organism. Animal cells maintain a correct diploid chromosome number by equally segregating their chromosomes into two daughter cells at each mitotic division. Errors in mitotic chromosome segregation result in the production of aneuploid daughter cells (i.e., cells possessing an incorrect chromosome number). Aneuploidy occurring in germ cells is well known for causing severe genetic diseases (such as
Cellular mechanisms of aneuploidy and cancer
The idea that aneuploidy can lead to cancer is currently widely accepted [10], [11], [12] and supported by a number of studies showing that aneuploidy correlates with cell transformation [13], [14], tumor development in animal models [15], [16], and chemically-induced carcinogenesis [13], [17], [18].
Two alternative hypotheses have been proposed for how aneuploidy leading to cancer can arise. One of them proposes that the first step toward aneuploidy is tetraploidization, most likely arising by
Kinetochore mis-attachments and chromosome mis-segregation
For accurate chromosome segregation, sister kinetochores must interact, during mitosis, with microtubules from opposite spindle poles (amphitelic kinetochore orientation or amphitelic attachment) (Fig. 1A). However, studies in tissue culture cells have shown that erroneous orientation, such as monotelic, syntelic, and merotelic attachments, can occur in early mitosis.
Cellular and molecular mechanisms of merotelic kinetochore formation and correction
Merotelic kinetochore orientation occurs at some base-line levels in various cell types in culture. For some cell lines, such as PtK1 cells, such frequencies have been determined at various stages of mitosis and it is known that merotelic attachments are very frequent in early mitosis, with over 30% of the cell possessing at least one merotelic kinetochore [40]. In other cell types, the occurrence in early mitosis is not known, but the presence of anaphase lagging chromosomes (0.5% in human
Merotelic kinetochore orientation in cancer cells
Although merotelic kinetochore orientation in cancer has not been extensively investigated, a number of studies have identified multipolar mitotic spindles [25], [26], [27], [28], [71], [72], [73], [74], [75], [76] and anaphase lagging chromosomes [28], [74], [75], [122], [123] in cancer cells.
As described in the previous section, multipolar spindle assembly results in high rates of merotelic attachments and increased frequencies of anaphase lagging chromosomes [64], [65]. However, lagging
Conclusions and perspectives
Although a correlation between aneuploidy and cancer is currently widely acknowledged, the actual role that aneuploidy plays in cancer development and/or progression is still a matter of debate. One debated subject is the way aneuploidy initially arises in dividing cells. One leading hypothesis in the field suggests that polyploidization is the first step toward aneuploidy [19], [20], [21]. A second hypothesis suggests instead that aneuploidy initially arises by gain or loss of one or few
Acknowledgements
I would like to thank Christophe Hirel for the technical assistance; the College of Science and the Department of Biological Sciences of Virginia Tech, and the Jeffress Memorial Trust for funding.
References (123)
- et al.
Chromosome segregation and genomic stability
Curr. Opin. Genet. Dev.
(2004) - et al.
Non-disjunction events induced by albendazole in human cells
Mutat. Res.
(2007) - et al.
Does aneuploidy cause cancer?
Curr. Opin. Cell. Biol.
(2006) - et al.
Aneuploidy precedes and segregates with chemical carcinogenesis
Cancer Genet. Cytogenet.
(2000) - et al.
Aneuploidy acts both oncogenically and as a tumor suppressor
Cancer Cell.
(2007) - et al.
Correlation between centrosome abnormalities and chromosomal instability in human pancreatic cancer cells
Cancer Genet. Cytogenet.
(2001) - et al.
The vertebrate cell kinetochore and its roles during mitosis
Trends Cell. Biol.
(1998) - et al.
Stuck in division or passing through; what happens when cells cannot satisfy the spindle assembly checkpoint
Dev. Cell.
(2004) - et al.
Timing and checkpoints in the regulation of mitotic progression
Dev. Cell.
(2004) - et al.
The spindle checkpoint: tension versus attachment
Trends Cell. Biol.
(2005)
Anaphase spindle mechanics prevent mis-segregation of merotelically oriented chromosomes
Curr. Biol.
The kinetochore proteins Pcs1 and Mde4 and heterochromatin are required to prevent merotelic orientation
Curr. Biol.
Chromosomal biomarkers of genomic instability relevant to cancer
Drug Discov. Today
Use of the micronucleus assay with exfoliated epithelial cells as a biomarker for monitoring individuals at elevated risk of genetic damage and in chemoprevention trials
Mutat. Res.
Efficient mitosis in human cells lacking poleward microtubule flux
Curr. Biol.
Roles of DNA topoisomerases in chromosome segregation and mitosis
Mutat. Res.
Chromosomal instability syndrome of total premature chromatid separation with mosaic variegated aneuploidy is defective in mitotic-spindle checkpoint
Am. J. Hum. Genet.
Kinetochores and microtubules in multipolar mitosis and chromosome orientation
Exp. Cell. Res.
Molecular requirements for kinetochore-associated microtubule formation in mammalian cells
Curr. Biol.
The occurrence of chromosome segregational defects is an intrinsic and heritable property of oral squamous cell carcinoma cell lines
Cancer Genet. Cytogenet.
Aurora kinase promotes turnover of kinetochore microtubules to reduce chromosome segregation errors
Curr. Biol.
Kinetochore microtubule dynamics and attachment stability are regulated by Hec1
Cell
Inhibition of aurora B kinase blocks chromosome segregation, overrides the spindle checkpoint, and perturbs microtubule dynamics in mitosis
Curr. Biol.
The kinase activity of aurora B is required for kinetochore–microtubule interactions during mitosis
Curr. Biol.
Kin I kinesins are microtubule-destabilizing enzymes
Cell
Aurora B regulates MCAK at the mitotic centromere
Dev. Cell.
Aurora B phosphorylates centromeric MCAK and regulates its localization and microtubule depolymerization activity
Curr. Biol.
Aurora B is enriched at merotelic attachment sites, where it regulates MCAK
Curr. Biol.
To err (meiotically) is human: the genesis of human aneuploidy
Nat. Rev. Genet.
Concerning the origin of malignant tumours by Theodor Boveri. Translated and annotated by Henry Harris
J. Cell. Sci.
Mitelman database of chromosome aberrations in cancer
Genetic instability in colorectal cancers
Nature
Direct and indirect non-disjunction in the origin of trisomy in cultured human lymphocytes
Mutagenesis
Segregation of sex chromosomes in human lymphocytes
Mutagenesis
Increased aneusomy and long arm deletion of chromosomes 5 and 7 in the lymphocytes of Chinese workers exposed to benzene
Carcinogenesis
Multistep carcinogenesis: a chain reaction of aneuploidizations
Cell Cycle
Aneuploidy and cancer
Nature
Aneuploidy correlated 100% with chemical transformation of Chinese hamster cells
Proc. Natl. Acad. Sci. U. S. A.
MAD2 haplo-insufficiency causes premature anaphase and chromosome instability in mammalian cells
Nature
Rae1 is an essential mitotic checkpoint regulator that cooperates with Bub3 to prevent chromosome missegregation
J. Cell. Biol.
Slippage of mitotic arrest and enhanced tumor development in mice with BubR1 haploinsufficiency
Cancer Res.
Cytokinesis failure generating tetraploids promotes tumorigenesis in p53-null cells
Nature
Chromosome nondisjunction yields tetraploid rather than aneuploid cells in human cell lines
Nature
From polyploidy to aneuploidy, genome instability and cancer
Nat. Rev. Mol. Cell. Biol.
Aurora kinases: new targets for cancer therapy
Clin. Cancer Res.
Mechanism of Aurora-B degradation and its dependency on intact KEN and A-boxes: identification of an aneuploidy-promoting property
Mol. Cell. Biol.
Overexpression of aurora kinase A in mouse mammary epithelium induces genetic instability preceding mammary tumor formation
Oncogene
Centrosome amplification and instability occurs exclusively in aneuploid, but not in diploid colorectal cancer cell lines, and correlates with numerical chromosomal aberrations
Genes Chromosomes Cancer
Centrosome amplification drives chromosomal instability in breast tumor development
Proc. Natl. Acad. Sci. U. S. A.
Chromosomal instability and cytoskeletal defects in oral cancer cells
Proc. Natl. Acad. Sci. U. S. A.
Cited by (168)
Proliferative advantage of specific aneuploid cells drives evolution of tumor karyotypes
2023, Biophysical JournalCell cycle regulation of ER membrane biogenesis protects against chromosome missegregation
2021, Developmental CellCitation Excerpt :In agreement with this idea, mitotic chromosomes induced to persist in the peripheral ER are more likely to missegregate (Ferrandiz et al., 2021). Merotelic attachments go unnoticed by the SAC (Cimini, 2008) and are a major source of aneuploidy in cancer cells (Cimini, 2008; Cimini et al., 2002, 2001). In a merotelically oriented kinetochore, loss of attachment from one pole can allow the chromosome to biorient—forces from MTs on the attached kinetochore promote the chromosome to move so that the unattached kinetochore faces the proper spindle pole (Cimini, 2008; Cimini et al., 2003) (Figure 7).