Gisselsson, D;
Hakanson, U;
Stoller, P;
Marti, D;
Jin, Y;
Rosengren, AH;
Stewenius, Y;
... Panagopoulos, I; + view all
(2008)
When the Genome Plays Dice: Circumvention of the Spindle Assembly Checkpoint and Near-Random Chromosome Segregation in Multipolar Cancer Cell Mitoses.
PLOS ONE
, 3
(4)
, Article e1871. 10.1371/journal.pone.0001871.
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Abstract
Background: Normal cell division is coordinated by a bipolar mitotic spindle, ensuring symmetrical segregation of chromosomes. Cancer cells, however, occasionally divide into three or more directions. Such multipolar mitoses have been proposed to generate genetic diversity and thereby contribute to clonal evolution. However, this notion has been little validated experimentally.Principal Findings: Chromosome segregation and DNA content in daughter cells from multipolar mitoses were assessed by multiphoton cross sectioning and fluorescence in situ hybridization in cancer cells and non-neoplastic transformed cells. The DNA distribution resulting from multipolar cell division was found to be highly variable, with frequent nullisomies in the daughter cells. Time-lapse imaging of H2B/GFP-labelled multipolar mitoses revealed that the time from the initiation of metaphase to the beginning of anaphase was prolonged and that the metaphase plates often switched polarity several times before metaphase-anaphase transition. The multipolar metaphase-anaphase transition was accompanied by a normal reduction of cellular cyclin B levels, but typically occurred before completion of the normal separase activity cycle. Centromeric AURKB and MAD2 foci were observed frequently to remain on the centromeres of multipolar ana-telophase chromosomes, indicating that multipolar mitoses were able to circumvent the spindle assembly checkpoint with some sister chromatids remaining unseparated after anaphase. Accordingly, scoring the distribution of individual chromosomes in multipolar daughter nuclei revealed a high frequency of nondisjunction events, resulting in a near-binomial allotment of sister chromatids to the daughter cells.Conclusion: The capability of multipolar mitoses to circumvent the spindle assembly checkpoint system typically results in a near-random distribution of chromosomes to daughter cells. Spindle multipolarity could thus be a highly efficient generator of genetically diverse minority clones in transformed cell populations.
| Type: | Article |
|---|---|
| Title: | When the Genome Plays Dice: Circumvention of the Spindle Assembly Checkpoint and Near-Random Chromosome Segregation in Multipolar Cancer Cell Mitoses |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1371/journal.pone.0001871 |
| Publisher version: | http://dx.doi.org/10.1371/journal.pone.0001871 |
| Language: | English |
| Additional information: | © 2008 Gisselsson et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This study was supported by the Swedish Children's Cancer Foundation, the Swedish Cancer Society, the Swedish Research Council, the Swedish Medical Society, the Swiss National Science Foundation (Grant 3152A0-100431), the Lund University Hospital Donation Funds, the Gunnar Nilsson Cancer Foundation, the Medical Faculty of Lund University, the Crafoord Foundation, the Erik-Philip Sörensen Foundation, the Lundgren Foundation, and the Swärd Foundation. The funders had no role in the conduct of the study, or in the collection, analysis, interpretation of the data, or in the preparation, review, or approval of the manuscript. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/1314074 |
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