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Sci Rep. 2016 May 20;6:26342. doi: 10.1038/srep26342.

Distinctive features of single nucleotide alterations in induced pluripotent stem cells with different types of DNA repair deficiency disorders.

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Department of Systems BioMedicine, National Research Institute for Child Health and Development, Tokyo, 157-8535, Japan.
Department of Reproduction, National Research Institute for Child Health and Development, Tokyo, 157-8535, Japan.
Biotechnology Research Institute for Drug Discovery, National Institute of Advanced Industrial Science and Technology (AIST), Ibaraki, 305-8568, Japan.
Laboratory of Gene Regulation, Faculty of Medicine, University of Tsukuba, Ibaraki, 305-8575, Japan.
Nanobiotechnology and Molecular Biology Research Lab, Department of Food Science and Nutrition, College of Food Science and Agriculture, King Saud University, P.O. Box 2460, Riyadh, 11451, Saudi Arabia.
Department of Food Sciences and Nutrition, College of Food and Agricultural Sciences, King Saud University, P.O. Box 2460, Riyadh 11451, Saudi Arabia.
Department of Chemical and Materials Engineering, National Central University, No. 300, Jhongda RD., Jhongli, Taoyuan 32001, Taiwan.
College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia.
Department of BioSciences, Kitasato University School of Science, Kanagawa, 252-0373, Japan.
Department of Maternal-Fetal Biology, National Research Institute for Child Health and Development, Tokyo, 157-8535, Japan.
Research team for Geriatric Medicine (Vascular Medicine), Tokyo Metropolitan Institute of Gerontology, Tokyo, 173-0015, Japan.


Disease-specific induced pluripotent stem cells (iPSCs) have been used as a model to analyze pathogenesis of disease. In this study, we generated iPSCs derived from a fibroblastic cell line of xeroderma pigmentosum (XP) group A (XPA-iPSCs), a rare autosomal recessive hereditary disease in which patients develop skin cancer in the areas of skin exposed to sunlight. XPA-iPSCs exhibited hypersensitivity to ultraviolet exposure and accumulation of single-nucleotide substitutions when compared with ataxia telangiectasia-derived iPSCs that were established in a previous study. However, XPA-iPSCs did not show any chromosomal instability in vitro, i.e. intact chromosomes were maintained. The results were mutually compensating for examining two major sources of mutations, nucleotide excision repair deficiency and double-strand break repair deficiency. Like XP patients, XPA-iPSCs accumulated single-nucleotide substitutions that are associated with malignant melanoma, a manifestation of XP. These results indicate that XPA-iPSCs may serve a monitoring tool (analogous to the Ames test but using mammalian cells) to measure single-nucleotide alterations, and may be a good model to clarify pathogenesis of XP. In addition, XPA-iPSCs may allow us to facilitate development of drugs that delay genetic alteration and decrease hypersensitivity to ultraviolet for therapeutic applications.

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