Cancer-associated noncoding mutations affect RNA G-quadruplex-mediated regulation of gene expression

Abstract Cancer is a multifactorial disease driven by a combination of genetic and environmental factors. Many cancer driver mutations have been characterised in protein-coding regions of the genome. However, mutations in noncoding regions associated with cancer have been less investigated. G-quadru...

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Autores principales:	Mahdi Zeraati, Aaron L. Moye, Jason W. H. Wong, Dilmi Perera, Mark J. Cowley, Daniel U. Christ, Tracy M. Bryan, Marcel E. Dinger
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/59ab4a1d4af84fbd87536aa985af8b63
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spelling	oai:doaj.org-article:59ab4a1d4af84fbd87536aa985af8b632021-12-02T11:40:34ZCancer-associated noncoding mutations affect RNA G-quadruplex-mediated regulation of gene expression10.1038/s41598-017-00739-y2045-2322https://doaj.org/article/59ab4a1d4af84fbd87536aa985af8b632017-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-00739-yhttps://doaj.org/toc/2045-2322Abstract Cancer is a multifactorial disease driven by a combination of genetic and environmental factors. Many cancer driver mutations have been characterised in protein-coding regions of the genome. However, mutations in noncoding regions associated with cancer have been less investigated. G-quadruplex (G4) nucleic acids are four-stranded secondary structures formed in guanine-rich sequences and prevalent in the regulatory regions. In this study, we used published whole cancer genome sequence data to find mutations in cancer patients that overlap potential RNA G4-forming sequences in 5′ UTRs. Using RNAfold, we assessed the effect of these mutations on the thermodynamic stability of predicted RNA G4s in the context of full-length 5′ UTRs. Of the 217 identified mutations, we found that 33 are predicted to destabilise and 21 predicted to stabilise potential RNA G4s. We experimentally validated the effect of destabilising mutations in the 5′ UTRs of BCL2 and CXCL14 and one stabilising mutation in the 5′ UTR of TAOK2. These mutations resulted in an increase or a decrease in translation of these mRNAs, respectively. These findings suggest that mutations that modulate the G4 stability in the noncoding regions could act as cancer driver mutations, which present an opportunity for early cancer diagnosis using individual sequencing information.Mahdi ZeraatiAaron L. MoyeJason W. H. WongDilmi PereraMark J. CowleyDaniel U. ChristTracy M. BryanMarcel E. DingerNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-11 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Mahdi Zeraati Aaron L. Moye Jason W. H. Wong Dilmi Perera Mark J. Cowley Daniel U. Christ Tracy M. Bryan Marcel E. Dinger Cancer-associated noncoding mutations affect RNA G-quadruplex-mediated regulation of gene expression
description	Abstract Cancer is a multifactorial disease driven by a combination of genetic and environmental factors. Many cancer driver mutations have been characterised in protein-coding regions of the genome. However, mutations in noncoding regions associated with cancer have been less investigated. G-quadruplex (G4) nucleic acids are four-stranded secondary structures formed in guanine-rich sequences and prevalent in the regulatory regions. In this study, we used published whole cancer genome sequence data to find mutations in cancer patients that overlap potential RNA G4-forming sequences in 5′ UTRs. Using RNAfold, we assessed the effect of these mutations on the thermodynamic stability of predicted RNA G4s in the context of full-length 5′ UTRs. Of the 217 identified mutations, we found that 33 are predicted to destabilise and 21 predicted to stabilise potential RNA G4s. We experimentally validated the effect of destabilising mutations in the 5′ UTRs of BCL2 and CXCL14 and one stabilising mutation in the 5′ UTR of TAOK2. These mutations resulted in an increase or a decrease in translation of these mRNAs, respectively. These findings suggest that mutations that modulate the G4 stability in the noncoding regions could act as cancer driver mutations, which present an opportunity for early cancer diagnosis using individual sequencing information.
format	article
author	Mahdi Zeraati Aaron L. Moye Jason W. H. Wong Dilmi Perera Mark J. Cowley Daniel U. Christ Tracy M. Bryan Marcel E. Dinger
author_facet	Mahdi Zeraati Aaron L. Moye Jason W. H. Wong Dilmi Perera Mark J. Cowley Daniel U. Christ Tracy M. Bryan Marcel E. Dinger
author_sort	Mahdi Zeraati
title	Cancer-associated noncoding mutations affect RNA G-quadruplex-mediated regulation of gene expression
title_short	Cancer-associated noncoding mutations affect RNA G-quadruplex-mediated regulation of gene expression
title_full	Cancer-associated noncoding mutations affect RNA G-quadruplex-mediated regulation of gene expression
title_fullStr	Cancer-associated noncoding mutations affect RNA G-quadruplex-mediated regulation of gene expression
title_full_unstemmed	Cancer-associated noncoding mutations affect RNA G-quadruplex-mediated regulation of gene expression
title_sort	cancer-associated noncoding mutations affect rna g-quadruplex-mediated regulation of gene expression
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/59ab4a1d4af84fbd87536aa985af8b63
work_keys_str_mv	AT mahdizeraati cancerassociatednoncodingmutationsaffectrnagquadruplexmediatedregulationofgeneexpression AT aaronlmoye cancerassociatednoncodingmutationsaffectrnagquadruplexmediatedregulationofgeneexpression AT jasonwhwong cancerassociatednoncodingmutationsaffectrnagquadruplexmediatedregulationofgeneexpression AT dilmiperera cancerassociatednoncodingmutationsaffectrnagquadruplexmediatedregulationofgeneexpression AT markjcowley cancerassociatednoncodingmutationsaffectrnagquadruplexmediatedregulationofgeneexpression AT danieluchrist cancerassociatednoncodingmutationsaffectrnagquadruplexmediatedregulationofgeneexpression AT tracymbryan cancerassociatednoncodingmutationsaffectrnagquadruplexmediatedregulationofgeneexpression AT marceledinger cancerassociatednoncodingmutationsaffectrnagquadruplexmediatedregulationofgeneexpression
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Cancer-associated noncoding mutations affect RNA G-quadruplex-mediated regulation of gene expression

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