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Limiting replication stress during somatic cell reprogramming reduces genomic instability in induced pluripotent stem cells

Author

Listed:
  • Sergio Ruiz

    (Genomic Instability Group, Spanish National Cancer Research Centre, 3, Melchor Fernandez Almagro, 28029 Madrid, Spain)

  • Andres J. Lopez-Contreras

    (Genomic Instability Group, Spanish National Cancer Research Centre, 3, Melchor Fernandez Almagro, 28029 Madrid, Spain
    Present address: Center for Chromosomal Stability, Department of Cellular and Molecular Medicine, Panum Institute, University of Copenhagen, 2200 Copenhagen, Denmark)

  • Mathieu Gabut

    (Ontario Institute for Cancer Research
    University of Toronto
    Present address: Cancer Research Centre of Lyon (CRCL), INSERM U1052-CNRS UMR5286, Université de Lyon, Centre Léon Bérard, 69008 Lyon, France)

  • Rosa M. Marion

    (Telomeres and Telomerase Group, Spanish National Cancer Research Centre)

  • Paula Gutierrez-Martinez

    (Genomic Instability Group, Spanish National Cancer Research Centre, 3, Melchor Fernandez Almagro, 28029 Madrid, Spain)

  • Sabela Bua

    (Cellular Plasticity and Disease Modelling group, Institut Pasteur)

  • Oscar Ramirez

    (ICREA at the Institut de Biologia Evolutiva (Universitat Pompeu Fabra/CSIC))

  • Iñigo Olalde

    (ICREA at the Institut de Biologia Evolutiva (Universitat Pompeu Fabra/CSIC))

  • Sara Rodrigo-Perez

    (Genomic Instability Group, Spanish National Cancer Research Centre, 3, Melchor Fernandez Almagro, 28029 Madrid, Spain)

  • Han Li

    (Cellular Plasticity and Disease Modelling group, Institut Pasteur)

  • Tomas Marques-Bonet

    (ICREA at the Institut de Biologia Evolutiva (Universitat Pompeu Fabra/CSIC)
    Centro Nacional de Análisis Genómico (CNAG))

  • Manuel Serrano

    (Tumor Supression Group, Spanish National Cancer Research Centre)

  • Maria A. Blasco

    (Telomeres and Telomerase Group, Spanish National Cancer Research Centre)

  • Nizar N. Batada

    (Ontario Institute for Cancer Research
    University of Toronto)

  • Oscar Fernandez-Capetillo

    (Genomic Instability Group, Spanish National Cancer Research Centre, 3, Melchor Fernandez Almagro, 28029 Madrid, Spain)

Abstract

The generation of induced pluripotent stem cells (iPSC) from adult somatic cells is one of the most remarkable discoveries in recent decades. However, several works have reported evidence of genomic instability in iPSC, raising concerns on their biomedical use. The reasons behind the genomic instability observed in iPSC remain mostly unknown. Here we show that, similar to the phenomenon of oncogene-induced replication stress, the expression of reprogramming factors induces replication stress. Increasing the levels of the checkpoint kinase 1 (CHK1) reduces reprogramming-induced replication stress and increases the efficiency of iPSC generation. Similarly, nucleoside supplementation during reprogramming reduces the load of DNA damage and genomic rearrangements on iPSC. Our data reveal that lowering replication stress during reprogramming, genetically or chemically, provides a simple strategy to reduce genomic instability on mouse and human iPSC.

Suggested Citation

  • Sergio Ruiz & Andres J. Lopez-Contreras & Mathieu Gabut & Rosa M. Marion & Paula Gutierrez-Martinez & Sabela Bua & Oscar Ramirez & Iñigo Olalde & Sara Rodrigo-Perez & Han Li & Tomas Marques-Bonet & Ma, 2015. "Limiting replication stress during somatic cell reprogramming reduces genomic instability in induced pluripotent stem cells," Nature Communications, Nature, vol. 6(1), pages 1-8, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms9036
    DOI: 10.1038/ncomms9036
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    Cited by:

    1. Anchel de Jaime-Soguero & Janina Hattemer & Anja Bufe & Alexander Haas & Jeroen Berg & Vincent Batenburg & Biswajit Das & Barbara Marco & Stefania Androulaki & Nicolas Böhly & Jonathan J. M. Landry & , 2024. "Developmental signals control chromosome segregation fidelity during pluripotency and neurogenesis by modulating replicative stress," Nature Communications, Nature, vol. 15(1), pages 1-22, December.

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