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The presence of extra chromosomes leads to genomic instability

Author

Listed:
  • Verena Passerini

    (Max Planck Institute of Biochemistry, Am Klopferspitz 18
    Center for Integrated Protein Science Munich)

  • Efrat Ozeri-Galai

    (The Alexander Silberman Institute of Life Sciences, Edmond J. Safra Campus, Givat-Ram)

  • Mirjam S. de Pagter

    (Center for Molecular Medicine, University Medical Center Utrecht, Universiteitsweg 100)

  • Neysan Donnelly

    (Max Planck Institute of Biochemistry, Am Klopferspitz 18)

  • Sarah Schmalbrock

    (Max Planck Institute of Biochemistry, Am Klopferspitz 18)

  • Wigard P. Kloosterman

    (Center for Molecular Medicine, University Medical Center Utrecht, Universiteitsweg 100)

  • Batsheva Kerem

    (The Alexander Silberman Institute of Life Sciences, Edmond J. Safra Campus, Givat-Ram)

  • Zuzana Storchová

    (Max Planck Institute of Biochemistry, Am Klopferspitz 18
    Center for Integrated Protein Science Munich
    Technical University Kaiserslautern, Paul-Ehrlich Strasse, Building 24)

Abstract

Aneuploidy is a hallmark of cancer and underlies genetic disorders characterized by severe developmental defects, yet the molecular mechanisms explaining its effects on cellular physiology remain elusive. Here we show, using a series of human cells with defined aneuploid karyotypes, that gain of a single chromosome increases genomic instability. Next-generation sequencing and SNP-array analysis reveal accumulation of chromosomal rearrangements in aneuploids, with break point junction patterns suggestive of replication defects. Trisomic and tetrasomic cells also show increased DNA damage and sensitivity to replication stress. Strikingly, we find that aneuploidy-induced genomic instability can be explained by the reduced expression of the replicative helicase MCM2-7. Accordingly, restoring near-wild-type levels of chromatin-bound MCM helicase partly rescues the genomic instability phenotypes. Thus, gain of chromosomes triggers replication stress, thereby promoting genomic instability and possibly contributing to tumorigenesis.

Suggested Citation

  • Verena Passerini & Efrat Ozeri-Galai & Mirjam S. de Pagter & Neysan Donnelly & Sarah Schmalbrock & Wigard P. Kloosterman & Batsheva Kerem & Zuzana Storchová, 2016. "The presence of extra chromosomes leads to genomic instability," Nature Communications, Nature, vol. 7(1), pages 1-12, April.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms10754
    DOI: 10.1038/ncomms10754
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    Cited by:

    1. Lorenza Garribba & Giuseppina De Feudis & Valentino Martis & Martina Galli & Marie Dumont & Yonatan Eliezer & René Wardenaar & Marica Rosaria Ippolito & Divya Ramalingam Iyer & Andréa E. Tijhuis & Dia, 2023. "Short-term molecular consequences of chromosome mis-segregation for genome stability," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    2. M. Kyle Cromer & Valentin V. Barsan & Erich Jaeger & Mengchi Wang & Jessica P. Hampton & Feng Chen & Drew Kennedy & Jenny Xiao & Irina Khrebtukova & Ana Granat & Tiffany Truong & Matthew H. Porteus, 2022. "Ultra-deep sequencing validates safety of CRISPR/Cas9 genome editing in human hematopoietic stem and progenitor cells," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    3. Revati Darp & Marc A. Vittoria & Neil J. Ganem & Craig J. Ceol, 2022. "Oncogenic BRAF induces whole-genome doubling through suppression of cytokinesis," Nature Communications, Nature, vol. 13(1), pages 1-17, December.

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