title: Limiting replication stress during somatic cell reprogramming reduces genomic instability in induced pluripotent stem cells.
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.
authors: Genomic Instability Group, Spanish National Cancer Research Centre, 3, Melchor Fernandez Almagro, 28029 Madrid, Spain.
authors: Sergio
authors: S
authors: Ruiz
authors: Genomic Instability Group, Spanish National Cancer Research Centre, 3, Melchor Fernandez Almagro, 28029 Madrid, Spain.
authors: Andres J
authors: AJ
authors: Lopez-Contreras
authors: Ontario Institute for Cancer Research, Toronto, Ontario, Canada M5G 0A3.|Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada M5G 1L7.
authors: Mathieu
authors: M
authors: Gabut
authors: Telomeres and Telomerase Group, Spanish National Cancer Research Centre, 28029 Madrid, Spain.
authors: Rosa M
authors: RM
authors: Marion
authors: Genomic Instability Group, Spanish National Cancer Research Centre, 3, Melchor Fernandez Almagro, 28029 Madrid, Spain.
authors: Paula
authors: P
authors: Gutierrez-Martinez
authors: Cellular Plasticity and Disease Modelling group, Department of Developmental and Stem Cell Biology, Institut Pasteur, 75015 Paris, France.
authors: Sabela
authors: S
authors: Bua
authors: ICREA at the Institut de Biologia Evolutiva (Universitat Pompeu Fabra/CSIC), 08003 Barcelona, Spain.
authors: Oscar
authors: O
authors: Ramirez
authors: ICREA at the Institut de Biologia Evolutiva (Universitat Pompeu Fabra/CSIC), 08003 Barcelona, Spain.
authors: Iñigo
authors: I
authors: Olalde
authors: Genomic Instability Group, Spanish National Cancer Research Centre, 3, Melchor Fernandez Almagro, 28029 Madrid, Spain.
authors: Sara
authors: S
authors: Rodrigo-Perez
authors: Cellular Plasticity and Disease Modelling group, Department of Developmental and Stem Cell Biology, Institut Pasteur, 75015 Paris, France.
authors: Han
authors: H
authors: Li
authors: ICREA at the Institut de Biologia Evolutiva (Universitat Pompeu Fabra/CSIC), 08003 Barcelona, Spain.|Centro Nacional de Análisis Genómico (CNAG), 08028 Barcelona, Spain.
authors: Tomas
authors: T
authors: Marques-Bonet
authors: Tumor Supression Group, Spanish National Cancer Research Centre, 28029 Madrid, Spain.
authors: Manuel
authors: M
authors: Serrano
authors: Telomeres and Telomerase Group, Spanish National Cancer Research Centre, 28029 Madrid, Spain.
authors: Maria A
authors: MA
authors: Blasco
authors: Ontario Institute for Cancer Research, Toronto, Ontario, Canada M5G 0A3.|Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada M5G 1L7.
authors: Nizar N
authors: NN
authors: Batada
authors: Genomic Instability Group, Spanish National Cancer Research Centre, 3, Melchor Fernandez Almagro, 28029 Madrid, Spain.
authors: Oscar
authors: O
authors: Fernandez-Capetillo
mesh_terms: D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation / Q000502:physiology*; D065150:Cellular Reprogramming / Q000502:physiology*; D000071877:Checkpoint Kinase 1; D004247:DNA / Q000235:genetics; D005347:Fibroblasts / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology; D042822:Genomic Instability / Q000502:physiology*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D009693:Nucleic Acid Hybridization; D010957:Plasmids; D017354:Point Mutation; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D013312:Stress, Physiological / Q000502:physiology*
chemical_list: D004247:DNA; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse