Micronuclei-based model system reveals functional consequences of chromothripsis in human cells

  1. Maja Kneissig
  2. Kristina Keuper
  3. Mirjam S de Pagter
  4. Markus J van Roosmalen
  5. Jana Martin
  6. Hannah Otto
  7. Verena Passerini
  8. Aline Campos Sparr
  9. Ivo Renkens
  10. Fenna Kropveld
  11. Anand Vasudevan
  12. Jason M Sheltzer
  13. Wigard P Kloosterman
  14. Zuzana Storchova  Is a corresponding author
  1. Technische Universität Kaiserslautern, Germany
  2. University Medical Center Utrecht, Netherlands
  3. Max Planck Institute of Biochemistry, Germany
  4. 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.

The following data sets were generated

Article and author information

Author details

  1. Maja Kneissig

    Department of Molecular Genetics, Technische Universität Kaiserslautern, Kaiserslautern, Germany
    Competing interests
    The authors declare that no competing interests exist.
  2. Kristina Keuper

    Department of Molecular Genetics, Technische Universität Kaiserslautern, Kaiserslautern, Germany
    Competing interests
    The authors declare that no competing interests exist.
  3. Mirjam S de Pagter

    Department of Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  4. Markus J van Roosmalen

    Department of Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  5. Jana Martin

    Department of Molecular Genetics, Technische Universität Kaiserslautern, Kaiserslautern, Germany
    Competing interests
    The authors declare that no competing interests exist.
  6. Hannah Otto

    Department of Molecular Genetics, Technische Universität Kaiserslautern, Kaiserslautern, Germany
    Competing interests
    The authors declare that no competing interests exist.
  7. Verena Passerini

    Max Planck Institute of Biochemistry, Martinsried, Germany
    Competing interests
    The authors declare that no competing interests exist.
  8. Aline Campos Sparr

    Max Planck Institute of Biochemistry, Martinsried, Germany
    Competing interests
    The authors declare that no competing interests exist.
  9. Ivo Renkens

    Department of Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  10. Fenna Kropveld

    Department of Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  11. Anand Vasudevan

    Cold Spring Harbor Laboratory, Cold Spring Harbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Jason M Sheltzer

    Cold Spring Harbor Laboratory, Cold Spring Harbor, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1381-1323
  13. Wigard P Kloosterman

    Department of Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  14. Zuzana Storchova

    Department of Molecular Genetics, Technische Universität Kaiserslautern, Kaiserslautern, Germany
    For correspondence
    storchova@bio.uni-kl.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2376-7047

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

  1. Silke Hauf, Virginia Tech, United States

Version history

  1. Received: July 17, 2019
  2. Accepted: November 23, 2019
  3. Accepted Manuscript published: November 28, 2019 (version 1)
  4. 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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  1. Maja Kneissig
  2. Kristina Keuper
  3. Mirjam S de Pagter
  4. Markus J van Roosmalen
  5. Jana Martin
  6. Hannah Otto
  7. Verena Passerini
  8. Aline Campos Sparr
  9. Ivo Renkens
  10. Fenna Kropveld
  11. Anand Vasudevan
  12. Jason M Sheltzer
  13. Wigard P Kloosterman
  14. Zuzana Storchova
(2019)
Micronuclei-based model system reveals functional consequences of chromothripsis in human cells
eLife 8:e50292.
https://doi.org/10.7554/eLife.50292

Share this article

https://doi.org/10.7554/eLife.50292

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