Induction of cryptic pre-mRNA splice-switching by antisense oligonucleotides

Abstract Antisense oligomers (AOs) are increasingly being used to modulate RNA splicing in live cells, both for research and for the development of therapeutics. While the most common intended effect of these AOs is to induce skipping of whole exons, rare examples are emerging of AOs that induce ski...

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Autores principales:	Kristin A. Ham, Niall P. Keegan, Craig S. McIntosh, May T. Aung-Htut, Khine Zaw, Kane Greer, Sue Fletcher, Steve D. Wilton
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/5312637696694b37aa54f9c7ed7d275a
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spelling	oai:doaj.org-article:5312637696694b37aa54f9c7ed7d275a2021-12-02T16:50:24ZInduction of cryptic pre-mRNA splice-switching by antisense oligonucleotides10.1038/s41598-021-94639-x2045-2322https://doaj.org/article/5312637696694b37aa54f9c7ed7d275a2021-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-94639-xhttps://doaj.org/toc/2045-2322Abstract Antisense oligomers (AOs) are increasingly being used to modulate RNA splicing in live cells, both for research and for the development of therapeutics. While the most common intended effect of these AOs is to induce skipping of whole exons, rare examples are emerging of AOs that induce skipping of only part of an exon, through activation of an internal cryptic splice site. In this report, we examined seven AO-induced cryptic splice sites in six genes. Five of these cryptic splice sites were discovered through our own experiments, and two originated from other published reports. We modelled the predicted effects of AO binding on the secondary structure of each of the RNA targets, and how these alterations would in turn affect the accessibility of the RNA to splice factors. We observed that a common predicted effect of AO binding was disruption of the exon definition signal within the exon’s excluded segment.Kristin A. HamNiall P. KeeganCraig S. McIntoshMay T. Aung-HtutKhine ZawKane GreerSue FletcherSteve D. WiltonNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Kristin A. Ham Niall P. Keegan Craig S. McIntosh May T. Aung-Htut Khine Zaw Kane Greer Sue Fletcher Steve D. Wilton Induction of cryptic pre-mRNA splice-switching by antisense oligonucleotides
description	Abstract Antisense oligomers (AOs) are increasingly being used to modulate RNA splicing in live cells, both for research and for the development of therapeutics. While the most common intended effect of these AOs is to induce skipping of whole exons, rare examples are emerging of AOs that induce skipping of only part of an exon, through activation of an internal cryptic splice site. In this report, we examined seven AO-induced cryptic splice sites in six genes. Five of these cryptic splice sites were discovered through our own experiments, and two originated from other published reports. We modelled the predicted effects of AO binding on the secondary structure of each of the RNA targets, and how these alterations would in turn affect the accessibility of the RNA to splice factors. We observed that a common predicted effect of AO binding was disruption of the exon definition signal within the exon’s excluded segment.
format	article
author	Kristin A. Ham Niall P. Keegan Craig S. McIntosh May T. Aung-Htut Khine Zaw Kane Greer Sue Fletcher Steve D. Wilton
author_facet	Kristin A. Ham Niall P. Keegan Craig S. McIntosh May T. Aung-Htut Khine Zaw Kane Greer Sue Fletcher Steve D. Wilton
author_sort	Kristin A. Ham
title	Induction of cryptic pre-mRNA splice-switching by antisense oligonucleotides
title_short	Induction of cryptic pre-mRNA splice-switching by antisense oligonucleotides
title_full	Induction of cryptic pre-mRNA splice-switching by antisense oligonucleotides
title_fullStr	Induction of cryptic pre-mRNA splice-switching by antisense oligonucleotides
title_full_unstemmed	Induction of cryptic pre-mRNA splice-switching by antisense oligonucleotides
title_sort	induction of cryptic pre-mrna splice-switching by antisense oligonucleotides
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/5312637696694b37aa54f9c7ed7d275a
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Induction of cryptic pre-mRNA splice-switching by antisense oligonucleotides

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