Nijmegen Breakage Syndrome fibroblasts and iPSCs: cellular models for uncovering disease-associated signaling pathways and establishing a screening platform for anti-oxidants

Abstract Nijmegen Breakage Syndrome (NBS) is associated with cancer predisposition, premature aging, immune deficiency, microcephaly and is caused by mutations in the gene coding for NIBRIN (NBN) which is involved in DNA damage repair. Dermal-derived fibroblasts from NBS patients were reprogrammed i...

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Autores principales:	Barbara Mlody, Wasco Wruck, Soraia Martins, Karl Sperling, James Adjaye
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/0fd702e9bc04461cab9a6c6e9d977027
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spelling	oai:doaj.org-article:0fd702e9bc04461cab9a6c6e9d9770272021-12-02T12:31:47ZNijmegen Breakage Syndrome fibroblasts and iPSCs: cellular models for uncovering disease-associated signaling pathways and establishing a screening platform for anti-oxidants10.1038/s41598-017-07905-22045-2322https://doaj.org/article/0fd702e9bc04461cab9a6c6e9d9770272017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-07905-2https://doaj.org/toc/2045-2322Abstract Nijmegen Breakage Syndrome (NBS) is associated with cancer predisposition, premature aging, immune deficiency, microcephaly and is caused by mutations in the gene coding for NIBRIN (NBN) which is involved in DNA damage repair. Dermal-derived fibroblasts from NBS patients were reprogrammed into induced pluripotent stem cells (iPSCs) in order to bypass premature senescence. The influence of antioxidants on intracellular levels of ROS and DNA damage were screened and it was found that EDHB-an activator of the hypoxia pathway, decreased DNA damage in the presence of high oxidative stress. Furthermore, NBS fibroblasts but not NBS-iPSCs were found to be more susceptible to the induction of DNA damage than their healthy counterparts. Global transcriptome analysis comparing NBS to healthy fibroblasts and NBS-iPSCs to embryonic stem cells revealed regulation of P53 in NBS fibroblasts and NBS-iPSCs. Cell cycle related genes were down-regulated in NBS fibroblasts. Furthermore, oxidative phosphorylation was down-regulated and glycolysis up-regulated specifically in NBS-iPSCs compared to embryonic stem cells. Our study demonstrates the utility of NBS-iPSCs as a screening platform for anti-oxidants capable of suppressing DNA damage and a cellular model for studying NBN de-regulation in cancer and microcephaly.Barbara MlodyWasco WruckSoraia MartinsKarl SperlingJames AdjayeNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-13 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Barbara Mlody Wasco Wruck Soraia Martins Karl Sperling James Adjaye Nijmegen Breakage Syndrome fibroblasts and iPSCs: cellular models for uncovering disease-associated signaling pathways and establishing a screening platform for anti-oxidants
description	Abstract Nijmegen Breakage Syndrome (NBS) is associated with cancer predisposition, premature aging, immune deficiency, microcephaly and is caused by mutations in the gene coding for NIBRIN (NBN) which is involved in DNA damage repair. Dermal-derived fibroblasts from NBS patients were reprogrammed into induced pluripotent stem cells (iPSCs) in order to bypass premature senescence. The influence of antioxidants on intracellular levels of ROS and DNA damage were screened and it was found that EDHB-an activator of the hypoxia pathway, decreased DNA damage in the presence of high oxidative stress. Furthermore, NBS fibroblasts but not NBS-iPSCs were found to be more susceptible to the induction of DNA damage than their healthy counterparts. Global transcriptome analysis comparing NBS to healthy fibroblasts and NBS-iPSCs to embryonic stem cells revealed regulation of P53 in NBS fibroblasts and NBS-iPSCs. Cell cycle related genes were down-regulated in NBS fibroblasts. Furthermore, oxidative phosphorylation was down-regulated and glycolysis up-regulated specifically in NBS-iPSCs compared to embryonic stem cells. Our study demonstrates the utility of NBS-iPSCs as a screening platform for anti-oxidants capable of suppressing DNA damage and a cellular model for studying NBN de-regulation in cancer and microcephaly.
format	article
author	Barbara Mlody Wasco Wruck Soraia Martins Karl Sperling James Adjaye
author_facet	Barbara Mlody Wasco Wruck Soraia Martins Karl Sperling James Adjaye
author_sort	Barbara Mlody
title	Nijmegen Breakage Syndrome fibroblasts and iPSCs: cellular models for uncovering disease-associated signaling pathways and establishing a screening platform for anti-oxidants
title_short	Nijmegen Breakage Syndrome fibroblasts and iPSCs: cellular models for uncovering disease-associated signaling pathways and establishing a screening platform for anti-oxidants
title_full	Nijmegen Breakage Syndrome fibroblasts and iPSCs: cellular models for uncovering disease-associated signaling pathways and establishing a screening platform for anti-oxidants
title_fullStr	Nijmegen Breakage Syndrome fibroblasts and iPSCs: cellular models for uncovering disease-associated signaling pathways and establishing a screening platform for anti-oxidants
title_full_unstemmed	Nijmegen Breakage Syndrome fibroblasts and iPSCs: cellular models for uncovering disease-associated signaling pathways and establishing a screening platform for anti-oxidants
title_sort	nijmegen breakage syndrome fibroblasts and ipscs: cellular models for uncovering disease-associated signaling pathways and establishing a screening platform for anti-oxidants
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/0fd702e9bc04461cab9a6c6e9d977027
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Nijmegen Breakage Syndrome fibroblasts and iPSCs: cellular models for uncovering disease-associated signaling pathways and establishing a screening platform for anti-oxidants

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