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

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, Manuel Serrano, Maria A. Blasco, Nizar N. Batada () and Oscar Fernandez-Capetillo ()
Additional contact information
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
Mathieu Gabut: Ontario Institute for Cancer Research
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)
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
Oscar Fernandez-Capetillo: Genomic Instability Group, Spanish National Cancer Research Centre, 3, Melchor Fernandez Almagro, 28029 Madrid, Spain

Nature Communications, 2015, vol. 6, issue 1, 1-8

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms9036

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