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Embryonic Stem Cells/Induced Pluripotent Stem Cells
Version of Record online: 20 AUG 2012
Copyright © 2012 AlphaMed Press
Volume 30, Issue 9, pages 1901–1910, September 2012
How to Cite
Hyka-Nouspikel, N., Desmarais, J., Gokhale, P. J., Jones, M., Meuth, M., Andrews, P. W. and Nouspikel, T. (2012), Deficient DNA Damage Response and Cell Cycle Checkpoints Lead to Accumulation of Point Mutations in Human Embryonic Stem Cells. STEM CELLS, 30: 1901–1910. doi: 10.1002/stem.1177
Author contributions: N.H.-N.: conception and design, collection and/or assembly of data, data analysis and interpretation, manuscript writing, and final approval of manuscript; T.N.: conception and design, financial support, collection and/or assembly of data, data analysis and interpretation, manuscript writing, and final approval of manuscript; M.M. and P.W.A.: financial support, provision of study materials, data analysis and interpretation, and final approval of manuscript; J.D.: provision of study materials, collection and/or assembly of data, and final approval of manuscript; P.J.G. and M.J.: collection and/or assembly of data, data analysis and interpretation, and final approval of manuscript.
Disclosure of potential conflicts of interest is found at the end of this article.
First published online in STEM CELLSEXPRESS July 20, 2012.
- Issue online: 20 AUG 2012
- Version of Record online: 20 AUG 2012
- Accepted manuscript online: 20 JUL 2012 09:48AM EST
- Manuscript Accepted: 21 MAY 2012
- Manuscript Received: 23 JAN 2012
- Yorkshire Cancer Research. Grant Numbers: PP005, S298
- U.K. Medical Research Council. Grant Number: G0700785
- fellowship from the Fonds de recherches du Québec—Santé
- Human embryonic stem cells;
- Point mutations;
- Cell cycle checkpoints;
- DNA damage;
- Nucleotide excision repair;
Human embryonic stem cells (hESCs) tend to lose genomic integrity during long periods of culture in vitro and to acquire a cancer-like phenotype. In this study, we aim at understanding the contribution of point mutations to the adaptation process and at providing a mechanistic explanation for their accumulation. We observed that, due to the absence of p21/Waf1/Cip1, cultured hESCs lack proper cell cycle checkpoints and are vulnerable to the kind of DNA damage usually repaired by the highly versatile nucleotide excision repair (NER) pathway. In response to UV-induced DNA damage, the majority of hESCs succumb to apoptosis; however, a subpopulation continues to proliferate, carrying damaged DNA and accumulating point mutations with a typical UV-induced signature. The UV-resistant cells retain their proliferative capacity and potential for pluripotent differentiation and are markedly less apoptotic to subsequent UV exposure. These findings demonstrate that, due to deficient DNA damage response, the modest NER activity in hESCs is insufficient to prevent increased mutagenesis. This provides for the appearance of genetically aberrant hESCs, paving the way for further major genetic changes. Stem Cells2012;30:1901–1910