Micronuclei-based model system reveals functional consequences of chromothripsis in human cells
- Technische Universität Kaiserslautern, Germany
- University Medical Center Utrecht, Netherlands
- Max Planck Institute of Biochemistry, Germany
- Cold Spring Harbor Laboratory, United States
Abstract
Cancer cells often harbor chromosomes in abnormal numbers and with aberrant structure. The consequences of these chromosomal aberrations are difficult to study in cancer, and therefore several model systems have been developed in recent years. We show that human cells with extra chromosome engineered via microcell-mediated chromosome transfer often gain massive chromosomal rearrangements. The rearrangements arose by chromosome shattering and rejoining as well as by replication-dependent mechanisms. We show that the isolated micronuclei lack functional lamin B1 and become prone to envelope rupture, which leads to DNA damage and aberrant replication. The presence of functional lamin B1 partly correlates with micronuclei size, suggesting that the proper assembly of nuclear envelope might be sensitive to membrane curvature. The chromosomal rearrangements in trisomic cells provide growth advantage compared to cells without rearrangements. Our model system enables to study mechanisms of massive chromosomal rearrangements of any chromosome and their consequences in human cells.
Data availability
High throughput data are available in public repositories. The SNP array data set supporting the results of this article is available in the Gene Expression Omnibus under the accession number GSE71979; the WGS data set supporting the results of this article is available in the European Nucleotide Archive repository under the accession number PRJEB10264. All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figure 1. Source data files for additional Figures are in preparation and will be associated with the article if accepted.
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Induced genomic rearrangements and chromothripsis by micronucleus-mediated chromosome transferNCBI Gene Expression Omnibus, GSE71979.
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Whole genome sequencing of cell lines generated with micronucleus mediated chromosome transferEuropean Nucleotide Archive, PRJEB10264.
Article and author information
Author details
Funding
Deutsche Forschungsgemeinschaft (Sto 918 - 5/1)
- Markus J van Roosmalen
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Silke Hauf, Virginia Tech, United States
Publication history
- Received: July 17, 2019
- Accepted: November 23, 2019
- Accepted Manuscript published: November 28, 2019 (version 1)
- Version of Record published: December 13, 2019 (version 2)
Copyright
© 2019, Kneissig et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Micronuclei-based model system reveals functional consequences of chromothripsis in human cells
eLife 8:e50292.
https://doi.org/10.7554/eLife.50292
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