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Nat Commun. 2015 Aug 21;6:8036. doi: 10.1038/ncomms9036.

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

Author information

1
Genomic Instability Group, Spanish National Cancer Research Centre, 3, Melchor Fernandez Almagro, 28029 Madrid, Spain.
2
Ontario Institute for Cancer Research, Toronto, Ontario, Canada M5G 0A3.
3
Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada M5G 1L7.
4
Telomeres and Telomerase Group, Spanish National Cancer Research Centre, 28029 Madrid, Spain.
5
Cellular Plasticity and Disease Modelling group, Department of Developmental and Stem Cell Biology, Institut Pasteur, 75015 Paris, France.
6
ICREA at the Institut de Biologia Evolutiva (Universitat Pompeu Fabra/CSIC), 08003 Barcelona, Spain.
7
Centro Nacional de Análisis Genómico (CNAG), 08028 Barcelona, Spain.
8
Tumor Supression Group, Spanish National Cancer Research Centre, 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.

PMID:
26292731
PMCID:
PMC4560784
DOI:
10.1038/ncomms9036
[Indexed for MEDLINE]
Free PMC Article

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