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Genome stability is ensured by temporal control of kinetochore–microtubule dynamics

Abstract

Most solid tumours are aneuploid and many frequently mis-segregate chromosomes. This chromosomal instability is commonly caused by persistent mal-oriented attachment of chromosomes to spindle microtubules. Chromosome segregation requires stable microtubule attachment at kinetochores, yet those attachments must be sufficiently dynamic to permit correction of mal-orientations. How this balance is achieved is unknown, and the permissible boundaries of attachment stability versus dynamics essential for genome stability remain poorly understood. Here we show that two microtubule-depolymerizing kinesins, Kif2b and MCAK, stimulate kinetochore–microtubule dynamics during distinct phases of mitosis to correct mal-orientations. Few-fold reductions in kinetochore–microtubule turnover, particularly in early mitosis, induce severe chromosome segregation defects. In addition, we show that stimulation of microtubule dynamics at kinetochores restores stability to chromosomally unstable tumour cell lines, establishing a causal relationship between deregulation of kinetochore–microtubule dynamics and chromosomal instability. Thus, temporal control of microtubule attachment to chromosomes during mitosis is central to genome stability in human cells.

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Figure 1: Lagging chromosomes in the absence of Kif2b and MCAK.
Figure 2: Kif2b is required for correction of attachment errors.
Figure 3: Kinetochore localization of GFP–Kif2b is sensitive to the Aurora inhibitor hesperadin.
Figure 4: Temporal regulation of kinetochore-microtubule dynamics.
Figure 5: Suppression of chromosome mis-segregation in cancer cell lines.

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Acknowledgements

We thank Linda Wordeman (University of Washington) for providing plasmids encoding GFP-tagged proteins, Tarun Kapoor for providing Hesperadin, and Kevin Sullivan for providing the CenpB–GFP U2OS cells. This work was supported by National Institutes of Health grants GM51542 to D.A.C. and GM008704 to S.L.T.

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All authors contributed to project planning and data analysis. S.F.B., S.L.T. and A.L.M. contributed to the experimental work.

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Correspondence to Duane A. Compton.

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Bakhoum, S., Thompson, S., Manning, A. et al. Genome stability is ensured by temporal control of kinetochore–microtubule dynamics. Nat Cell Biol 11, 27–35 (2009). https://doi.org/10.1038/ncb1809

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