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; Oscar Fernandez-Capetillo

doi:10.1038/ncomms9036

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, Oscar Fernandez-Capetillo

55 Citations (Scopus)

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.

Original language	English
Journal	Nature Communications
Volume	6
Pages (from-to)	8036
ISSN	2041-1723
DOIs	https://doi.org/10.1038/ncomms9036
Publication status	Published - 21 Aug 2015
Externally published	Yes

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Ruiz, S., Lopez-Contreras, A. J., Gabut, M., Marion, R. M., Gutierrez-Martinez, P., Bua, S., Ramirez, O., Olalde, I., Rodrigo-Perez, S., Li, H., Marques-Bonet, T., Serrano, M., Blasco, M. A., Batada, N. N., & Fernandez-Capetillo, O. (2015). Limiting replication stress during somatic cell reprogramming reduces genomic instability in induced pluripotent stem cells. Nature Communications, 6, 8036. https://doi.org/10.1038/ncomms9036

Ruiz, S, Lopez-Contreras, AJ, Gabut, M, Marion, RM, Gutierrez-Martinez, P, Bua, S, Ramirez, O, Olalde, I, Rodrigo-Perez, S, Li, H, Marques-Bonet, T, Serrano, M, Blasco, MA, Batada, NN & Fernandez-Capetillo, O 2015, 'Limiting replication stress during somatic cell reprogramming reduces genomic instability in induced pluripotent stem cells', Nature Communications, vol. 6, pp. 8036. https://doi.org/10.1038/ncomms9036

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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.",

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AU - Ruiz, Sergio

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AU - Marion, Rosa M

AU - Gutierrez-Martinez, Paula

AU - Bua, Sabela

AU - Ramirez, Oscar

AU - Olalde, Iñigo

AU - Rodrigo-Perez, Sara

AU - Li, Han

AU - Marques-Bonet, Tomas

AU - Serrano, Manuel

AU - Blasco, Maria A

AU - Batada, Nizar N

AU - Fernandez-Capetillo, Oscar

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N2 - 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.

AB - 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.

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DO - 10.1038/ncomms9036

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SN - 2041-1723

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SP - 8036

JO - Nature Communications

JF - Nature Communications

ER -

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

Abstract

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