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

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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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Acknowledgments

We would like to thank Guangbo Chen and members of the Rong Li lab for their insightful discussions, Gary Gorbsky for comments on the manuscript, and Mary Toth for help with review preparation. This work was supported by the NIH grant RO1-GM059964 to Rong Li. Tamara Potapova was supported by a Postdoctoral Fellowship, PF-12-129-01-CCG from the American Cancer Society. Jin Zhu is a graduate student registered with the Open University.

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  1. Stowers Institute for Medical Research, Kansas City, MO, 64110, USA

    Tamara A. Potapova, Jin Zhu & Rong Li

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  1. Tamara A. Potapova
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Correspondence to Tamara A. Potapova.

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Authors Tamara A. Potapova and Jin Zhu contributed equally to this work.

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Potapova, T.A., Zhu, J. & Li, R. Aneuploidy and chromosomal instability: a vicious cycle driving cellular evolution and cancer genome chaos. Cancer Metastasis Rev 32, 377–389 (2013). https://doi.org/10.1007/s10555-013-9436-6

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