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Chromosome nondisjunction yields tetraploid rather than aneuploid cells in human cell lines

Nature volume 437, pages 1038–1042 (2005)Cite this article

Abstract

Although mutations in cell cycle regulators or spindle proteins can perturb chromosome segregation1,2,3,4,5,6,7, the causes and consequences of spontaneous mitotic chromosome nondisjunction in human cells are not well understood. It has been assumed that nondisjunction of a chromosome during mitosis will yield two aneuploid daughter cells. Here we show that chromosome nondisjunction is tightly coupled to regulation of cytokinesis in human cell lines, such that nondisjunction results in the formation of tetraploid rather than aneuploid cells. We observed that spontaneously arising binucleated cells exhibited chromosome mis-segregation rates up to 166-fold higher than the overall mitotic population. Long-term imaging experiments indicated that most binucleated cells arose through a bipolar mitosis followed by regression of the cleavage furrow hours later. Nondisjunction occurred with high frequency in cells that became binucleated by furrow regression, but not in cells that completed cytokinesis to form two mononucleated cells. Our findings indicate that nondisjunction does not directly yield aneuploid cells, but rather tetraploid cells that may subsequently become aneuploid through further division. The coupling of spontaneous segregation errors to furrow regression provides a potential explanation for the prevalence of hyperdiploid chromosome number and centrosome amplification observed in many cancers8,9.

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Figure 1: Chromosome mis-segregation occurs at high frequency in spontaneously arising binucleated cells.
Figure 2: Nondisjunction occurs with high frequency in cells that become binucleated by furrow regression, but not in cells that complete cytokinesis.
Figure 3: Fates of mononucleated and binucleated N/TERT-1 and HeLa cells determined by long-term imaging.
Figure 4: Model summarizing the relationship of chromosome mis-segregation in the regulation of cytokinesis, and subsequent possible fates of resulting binucleated cells.

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Acknowledgements

We thank J. Rheinwald for N/TERT-1 cells, W. Hahn for PrEC cells, J. Waters and the Nikon Imaging Center at Harvard Medical School for assistance and equipment, T. Mitchison for discussions, and D. Pellman, A. Amon, D. Moazed and P. Jackson for comments on the manuscript. This work was supported by the Harry C. McKenzie Family Foundation and the Harvard-Armenise Foundation. R.W.K. is a Damon Runyon-Walter Winchell Foundation Scholar.

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  1. Qinghua Shi

    Present address: Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, 230026, China

Authors and Affiliations

  1. Department of Cell Biology, Harvard Medical School, 240 Longwood Ave, Massachusetts, 02115, Boston, USA

    Qinghua Shi & Randall W. King

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  1. Qinghua Shi
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Correspondence to Randall W. King.

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Supplementary information

Supplementary Notes

This file contains Supplementary Methods, Supplementary Figures S1–S7, Supplementary Tables S1–S3, and legends for the Supplementary Videos. (PDF 2866 kb)

Supplementary Movie S1

This movie shows a mononucleated HeLa cell expressing an H2B–GFP fusion protein that undergoes a normal bipolar mitosis. (MOV 377 kb)

Supplementary Movie S2

This movie shows the generation of a binucleated cell through normal bipolar mitosis followed by cleavage furrow regression. (MOV 2040 kb)

Supplementary Movie S3

This movie shows a second example of the generation of a binucleated cell through normal bipolar mitosis followed by cleavage furrow regression. (MOV 1223 kb)

Supplementary Movie S4

This movie shows the generation of a binucleated cell through abnormal mitosis of a mononucleated cell. (MOV 934 kb)

Supplementary Movie S5

This movie shows the generation of a binucleated cell through fusion of two newly generated mononucleated cells. (MOV 1161 kb)

Supplementary Movie S6

This movie shows a binucleated cell that divides with a tetrapolar mitosis to produce two binucleated cells. (MOV 1063 kb)

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Shi, Q., King, R. Chromosome nondisjunction yields tetraploid rather than aneuploid cells in human cell lines. Nature 437, 1038–1042 (2005). https://doi.org/10.1038/nature03958

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