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Review
. 2013 Dec;32(3-4):377-89.
doi: 10.1007/s10555-013-9436-6.

Aneuploidy and chromosomal instability: a vicious cycle driving cellular evolution and cancer genome chaos

Tamara A Potapova  1 , Jin Zhu, Rong Li
Affiliations
Review

Aneuploidy and chromosomal instability: a vicious cycle driving cellular evolution and cancer genome chaos

Tamara A Potapova et al. Cancer Metastasis Rev. 2013 Dec.

Abstract

Aneuploidy and chromosomal instability frequently co-exist, and aneuploidy is recognized as a direct outcome of chromosomal instability. However, chromosomal instability is widely viewed as a consequence of mutations in genes involved in DNA replication, chromosome segregation, and cell cycle checkpoints. Telomere attrition and presence of extra centrosomes have also been recognized as causative for errors in genomic transmission. Here, we examine recent studies suggesting that aneuploidy itself can be responsible for the procreation of chromosomal instability. Evidence from both yeast and mammalian experimental models suggests that changes in chromosome copy number can cause changes in dosage of the products of many genes located on aneuploid chromosomes. These effects on gene expression can alter the balanced stoichiometry of various protein complexes, causing perturbations of their functions. Therefore, phenotypic consequences of aneuploidy will include chromosomal instability if the balanced stoichiometry of protein machineries responsible for accurate chromosome segregation is affected enough to perturb the function. The degree of chromosomal instability will depend on specific karyotypic changes, which may be due to dosage imbalances of specific genes or lack of scaling between chromosome segregation load and the capacity of the mitotic system. We propose that the relationship between aneuploidy and chromosomal instability can be envisioned as a "vicious cycle," where aneuploidy potentiates chromosomal instability leading to further karyotype diversity in the affected population.

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Figures

Figure 1
Figure 1. Perturbations of mitotic protein machinery lead to chromosome instability
During mitosis condensed chromosomes (violet) form stable kinetochore (blue)-microtubule (green) attachments, align on the metaphase plate, and then segregate to opposite spindle poles in anaphase. Gene dosage imbalance can lead to defects in spindle assembly checkpoint and proper formation of the mitotic spindle. Spindle assembly checkpoint is a surveillance mechanism that generates the “delay anaphase” signal in response to unattached kinetochores. Defects in spindle assembly checkpoint allow anaphase to proceed despite the presence of a misaligned chromosome (yellow) whose kinetochores (red) are not stably attached to microtubules. Unattached sister chromatids cannot segregate to opposite spindle poles during anaphase and wind up in one of the daughter cells. Merotelically attached chromosome (magenta), where a single kinetochore is attached to microtubules from both spindle poles, can be a consequence of defects in mitotic spindle formation and microtubule dynamics. Merotelic attachments can evade mitotic spindle checkpoint surveillance but form lagging chromosomes that tend to missegregate and can disrupt the last step in cytokinesis - abscission. The failure to segregate properly leads to altered chromosome copy number in daughter cells: both copies of the unattached or lagging chromosomes end up in one cell while the other cell lacks a copy. Unattached and lagging chromosomes can form micronuclei – detached minute nuclei consisting of de-condensed DNA from missegregated chromosomes surrounded by the nuclear membrane. Micronuclei are prone to having defects in DNA replication, which adds to genomic instability. Chromosome missegregations, as well as protein dosage imbalances, can lead to cytokinesis failure and formation of tetraploid cells which are binucleate and contain twice the number of centrosomes (orange) as diploid cells. Tetraploid cells can also have micronuclei.
Figure 2
Figure 2. Vicious cycle of aneuploidy and chromosome instability
Aneuploidy (presence of extra or missing chromosomes) is a consequence of chromosome instability. Alterations in chromosome copy number in aneuploid cells produce proportional changes in the level of transcripts of genes located on aneuploid chromosomes. This largely translates in dosage changes of protein products of these genes, which can alter the balanced stoichiometry of various protein complexes or pathways leading to malfunctioning of corresponding biological processes. Stoichiometric imbalances in protein complexes or regulatory activities involved in mitosis can cause various defects in mitotic spindle formation, mitotic checkpoint and cytokinesis. These defects can lead to errors in chromosome segregation and tetraploidy, thus elevating the level of chromosome instability and leading to more aneuploidy.
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References

    1. Initial sequence of the chimpanzee genome and comparison with the human genome. Nature. 2005;437:69–87. - PubMed
    1. Dobzhansky Theodosius., editor. Genetics and the Origin of Species. 3. New York: Columbia University Press; 1951. pp. 73–118.
    1. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–674. - PubMed
    1. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57–70. - PubMed
    1. Anders K, Kudrna J, Keller K, Kinghorn B, Miller E, et al. A strategy for constructing aneuploid yeast strains by transient nondisjunction of a _target chromosome. BMC Genetics. 2009;10:36. - PMC - PubMed

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