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

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 pati...

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Veröffentlicht in:Scientific reports 2016-05, Vol.6 (1), p.26342, Article 26342
Hauptverfasser: Okamura, Kohji, Sakaguchi, Hironari, Sakamoto-Abutani, Rie, Nakanishi, Mahito, Nishimura, Ken, Yamazaki-Inoue, Mayu, Ohtaka, Manami, Periasamy, Vaiyapuri Subbarayan, Alshatwi, Ali Abdullah, Higuchi, Akon, Hanaoka, Kazunori, Nakabayashi, Kazuhiko, Takada, Shuji, Hata, Kenichiro, Toyoda, Masashi, Umezawa, Akihiro
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Sprache:eng
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Zusammenfassung: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.
ISSN:2045-2322
2045-2322
DOI:10.1038/srep26342