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Stem Cell Reports. 2017 Feb 14;8(2):432-445. doi: 10.1016/j.stemcr.2016.12.009. Epub 2017 Jan 5.

CtIP-Specific Roles during Cell Reprogramming Have Long-Term Consequences in the Survival and Fitness of Induced Pluripotent Stem Cells.

Author information

1
Andalusian Center for Molecular Biology and Regenerative Medicine (CABIMER), Seville 41092, Spain. Electronic address: daniel.gomez@cabimer.es.
2
Andalusian Center for Molecular Biology and Regenerative Medicine (CABIMER), Seville 41092, Spain; Department of Genetics, University of Seville, Seville 41012, Spain.
3
Tumour Suppression Group, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
4
Andalusian Center for Molecular Biology and Regenerative Medicine (CABIMER), Seville 41092, Spain; Department of Genetics, University of Seville, Seville 41012, Spain. Electronic address: pablo.huertas@cabimer.es.

Abstract

Acquired genomic instability is one of the major concerns for the clinical use of induced pluripotent stem cells (iPSCs). All reprogramming methods are accompanied by the induction of DNA damage, of which double-strand breaks are the most cytotoxic and mutagenic. Consequently, DNA repair genes seem to be relevant for accurate reprogramming to minimize the impact of such DNA damage. Here, we reveal that reprogramming is associated with high levels of DNA end resection, a critical step in homologous recombination. Moreover, the resection factor CtIP is essential for cell reprogramming and establishment of iPSCs, probably to repair reprogramming-induced DNA damage. Our data reveal a new role for DNA end resection in maintaining genomic stability during cell reprogramming, allowing DNA repair fidelity to be retained in both human and mouse iPSCs. Moreover, we demonstrate that reprogramming in a resection-defective environment has long-term consequences on stem cell self-renewal and differentiation.

KEYWORDS:

DNA resection; cell reprogramming; genetic instability; iPSC

PMID:
28065643
PMCID:
PMC5311465
DOI:
10.1016/j.stemcr.2016.12.009
[Indexed for MEDLINE]
Free PMC Article

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