Review
Merotelic kinetochore orientation, aneuploidy, and cancer

https://doi.org/10.1016/j.bbcan.2008.05.003Get rights and content

Abstract

Accurate chromosome segregation in mitosis is crucial to maintain a diploid chromosome number. A majority of cancer cells are aneuploid and chromosomally unstable, i.e. they tend to gain and lose chromosomes at each mitotic division. Chromosome mis-segregation can arise when cells progress through mitosis with mis-attached kinetochores. Merotelic kinetochore orientation, a type of mis-attachment in which a single kinetochore binds microtubules from two spindle poles rather than just one, can represent a particular threat for dividing cells, as: (i) it occurs frequently in early mitosis; (ii) it is not detected by the spindle assembly checkpoint (unlike other types of mis-attachments); (iii) it can lead to chromosome mis-segregation, and, hence, aneuploidy. A number of studies have recently started to unveil the cellular and molecular mechanisms involved in merotelic kinetochore formation and correction. Here, I review these studies and discuss the relevance of merotelic kinetochore orientation in cancer cell biology.

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.

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