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Exome sequencing identifies novel mutation signatures of UV radiation and trichostatin A in primary human keratinocytes

Canonical ultraviolet (UV) mutation type and spectra are traditionally defined by direct sequencing-based approaches to map mutations in a limited number of representative DNA elements. To obtain an unbiased view of genome wide UV mutation features, we performed whole exome-sequencing (WES) to profi...

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Autores principales: Shen, Yao, Ha, Wootae, Zeng, Wangyong, Queen, Dawn, Liu, Liang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7080724/
https://www.ncbi.nlm.nih.gov/pubmed/32188867
http://dx.doi.org/10.1038/s41598-020-61807-4
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author Shen, Yao
Ha, Wootae
Zeng, Wangyong
Queen, Dawn
Liu, Liang
author_facet Shen, Yao
Ha, Wootae
Zeng, Wangyong
Queen, Dawn
Liu, Liang
author_sort Shen, Yao
collection PubMed
description Canonical ultraviolet (UV) mutation type and spectra are traditionally defined by direct sequencing-based approaches to map mutations in a limited number of representative DNA elements. To obtain an unbiased view of genome wide UV mutation features, we performed whole exome-sequencing (WES) to profile single nucleotide substitutions in UVB-irradiated primary human keratinocytes. Cross comparison of UV mutation profiles under different UVB radiation conditions revealed that T > C transition was highly prevalent in addition to C > T transition. We also identified 5′-ACG-3′ as a common sequence motif of C > T transition. Furthermore, our analyses uncovered several recurring UV mutations following acute UVB radiation affecting multiple genes including HRNR, TRIOBP, KCNJ12, and KMT2C, which are frequently mutated in skin cancers, indicating their potential role as founding mutations in UV-induced skin tumorigenesis. Pretreatment with trichostatin A, a pan-histone deacetylase inhibitor that renders chromatin decondensation, significantly decreased the number of mutations in UVB-irradiated keratinocytes. Unexpectedly, we found trichostatin A to be a mutagen that caused DNA damage and mutagenesis at least partly through increased reactive oxidation. In summary, our study reveals new UV mutation features following acute UVB radiation and identifies novel UV mutation hotspots that may potentially represent founding driver mutations in skin cancer development.
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spelling pubmed-70807242020-03-23 Exome sequencing identifies novel mutation signatures of UV radiation and trichostatin A in primary human keratinocytes Shen, Yao Ha, Wootae Zeng, Wangyong Queen, Dawn Liu, Liang Sci Rep Article Canonical ultraviolet (UV) mutation type and spectra are traditionally defined by direct sequencing-based approaches to map mutations in a limited number of representative DNA elements. To obtain an unbiased view of genome wide UV mutation features, we performed whole exome-sequencing (WES) to profile single nucleotide substitutions in UVB-irradiated primary human keratinocytes. Cross comparison of UV mutation profiles under different UVB radiation conditions revealed that T > C transition was highly prevalent in addition to C > T transition. We also identified 5′-ACG-3′ as a common sequence motif of C > T transition. Furthermore, our analyses uncovered several recurring UV mutations following acute UVB radiation affecting multiple genes including HRNR, TRIOBP, KCNJ12, and KMT2C, which are frequently mutated in skin cancers, indicating their potential role as founding mutations in UV-induced skin tumorigenesis. Pretreatment with trichostatin A, a pan-histone deacetylase inhibitor that renders chromatin decondensation, significantly decreased the number of mutations in UVB-irradiated keratinocytes. Unexpectedly, we found trichostatin A to be a mutagen that caused DNA damage and mutagenesis at least partly through increased reactive oxidation. In summary, our study reveals new UV mutation features following acute UVB radiation and identifies novel UV mutation hotspots that may potentially represent founding driver mutations in skin cancer development. Nature Publishing Group UK 2020-03-18 /pmc/articles/PMC7080724/ /pubmed/32188867 http://dx.doi.org/10.1038/s41598-020-61807-4 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Shen, Yao
Ha, Wootae
Zeng, Wangyong
Queen, Dawn
Liu, Liang
Exome sequencing identifies novel mutation signatures of UV radiation and trichostatin A in primary human keratinocytes
title Exome sequencing identifies novel mutation signatures of UV radiation and trichostatin A in primary human keratinocytes
title_full Exome sequencing identifies novel mutation signatures of UV radiation and trichostatin A in primary human keratinocytes
title_fullStr Exome sequencing identifies novel mutation signatures of UV radiation and trichostatin A in primary human keratinocytes
title_full_unstemmed Exome sequencing identifies novel mutation signatures of UV radiation and trichostatin A in primary human keratinocytes
title_short Exome sequencing identifies novel mutation signatures of UV radiation and trichostatin A in primary human keratinocytes
title_sort exome sequencing identifies novel mutation signatures of uv radiation and trichostatin a in primary human keratinocytes
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7080724/
https://www.ncbi.nlm.nih.gov/pubmed/32188867
http://dx.doi.org/10.1038/s41598-020-61807-4
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