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A mechanism linking extra centrosomes to chromosomal instability

Abstract

Chromosomal instability (CIN) is a hallmark of many tumours and correlates with the presence of extra centrosomes1,2,3,4. However, a direct mechanistic link between extra centrosomes and CIN has not been established. It has been proposed that extra centrosomes generate CIN by promoting multipolar anaphase, a highly abnormal division that produces three or more aneuploid daughter cells. Here we use long-term live-cell imaging to demonstrate that cells with multiple centrosomes rarely undergo multipolar cell divisions, and the progeny of these divisions are typically inviable. Thus, multipolar divisions cannot explain observed rates of CIN. In contrast, we observe that CIN cells with extra centrosomes routinely undergo bipolar cell divisions, but display a significantly increased frequency of lagging chromosomes during anaphase. To define the mechanism underlying this mitotic defect, we generated cells that differ only in their centrosome number. We demonstrate that extra centrosomes alone are sufficient to promote chromosome missegregation during bipolar cell division. These segregation errors are a consequence of cells passing through a transient ‘multipolar spindle intermediate’ in which merotelic kinetochore–microtubule attachment errors accumulate before centrosome clustering and anaphase. These findings provide a direct mechanistic link between extra centrosomes and CIN, two common characteristics of solid tumours. We propose that this mechanism may be a common underlying cause of CIN in human cancer.

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Figure 1: Multipolar cell divisions are rare and the progeny are typically inviable.
Figure 2: Extra centrosomes correlate with increases in lagging chromosomes.
Figure 3: Extra centrosomes promote chromosome missegregation.
Figure 4: ‘Multipolar spindle intermediates’ promote merotelic attachment.

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Acknowledgements

We would like to thank D. Compton, R. King, D. Livingston, A. Manning, T. Rapoport, J. Shah, T. Stukenberg and members of the Pellman laboratory for comments and discussion of the manuscript; L. Cameron for setting up the confocal microscope; P. Schow for help with FACS; D. Neuberg for help with statistical analysis; C. King for help with the model figure; J. Iwasa for creating the animations; and L. Moreau and S. Thompson for technical advice on chromosome spreads and FISH analysis. Reagents were provided by D. Compton, S. Gollin, R. King, A. Khodjakov, E. Nigg and G.Wahl. N.J.G. is a fellow of the Leukemia and Lymphoma Society and D.P. is an HHMI Investigator. This work was supported by NIH grant GM083299.

Author Contributions N.J.G. and D.P. designed the experiments and wrote the manuscript. N.J.G. performed most of the experiments and data analysis. S.A.G. conceived and conducted experiments and performed data analysis, particularly for Fig. 4. D.P. supervised all aspects of the project. All authors discussed results and edited the manuscript.

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Correspondence to David Pellman.

Supplementary information

Supplementary Figures

This file contains Supplementary Figures 1-8 with Legends. (PDF 748 kb)

Supplementary Movie 1

This movie shows a representative SCC114 cell expressing H2B-GFP that undergoes a multipolar cell division to produce three aneuploid daughter cells. All three daughter cells die in the subsequent cell cycle. Images captured every 10 minutes. (MOV 463 kb)

Supplementary Movie 2

This movie shows a tetraploid RPE-1 cell stably expressing GFP-centrin and mRFP-H2B that undergoes a multipolar cell division. Numerous lagging chromosomes can be observed at anaphase. Images captured every 2 minutes. (MOV 3694 kb)

Supplementary Movie 3

This movie shows tetraploid RPE-1 cell stably expressing GFP-centrin and mRFP-H2B during mitosis. While the majority of chromosomes are aligned at the metaphase plate, a single polar chromosome can be observed bi-orienting between two semi-clustered centrosomes. Anaphase ensues before this chromosome aligns, resulting in a single chromosomes missegregation event. Images captured every 2 minutes. (MOV 3462 kb)

Supplementary Movie 4

This file contains a cartoon animation demonstrating that both syntelic and merotelic attachments errors accumulate when extra-centrosomal cells pass through a transient multipolar intermediate prior to centrosome clustering and anaphase. (MOV 5028 kb)

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Ganem, N., Godinho, S. & Pellman, D. A mechanism linking extra centrosomes to chromosomal instability. Nature 460, 278–282 (2009). https://doi.org/10.1038/nature08136

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