Molecular basis of differential 3' splice site sensitivity to anti-tumor drugs targeting U2 snRNP

Several splicing-modulating compounds, including Sudemycins and Spliceostatin A, display anti-tumor properties. Combining transcriptome, bioinformatic and mutagenesis analyses, we delineate sequence determinants of the differential sensitivity of 3' splice sites to these drugs. Sequences 5&...

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Detalles Bibliográficos
Autores: Vigevani, Luisa, 1985-, Gohr, André, Webb, Thomas R., Irimia Martínez, Manuel, Valcárcel, J. (Juan)
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2017
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:10230/34937
Acceso en línea:http://hdl.handle.net/10230/34937
http://dx.doi.org/10.1038/s41467-017-02007-z
Access Level:acceso abierto
Palabra clave:Drug development
Mechanism of action
Rna splicing
Small molecules
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spelling Molecular basis of differential 3' splice site sensitivity to anti-tumor drugs targeting U2 snRNPVigevani, Luisa, 1985-Gohr, AndréWebb, Thomas R.Irimia Martínez, ManuelValcárcel, J. (Juan)Drug developmentMechanism of actionRna splicingSmall moleculesSeveral splicing-modulating compounds, including Sudemycins and Spliceostatin A, display anti-tumor properties. Combining transcriptome, bioinformatic and mutagenesis analyses, we delineate sequence determinants of the differential sensitivity of 3' splice sites to these drugs. Sequences 5' from the branch point (BP) region strongly influence drug sensitivity, with additional functional BPs reducing, and BP-like sequences allowing, drug responses. Drug-induced retained introns are typically shorter, displaying higher GC content and weaker polypyrimidine-tracts and BPs. Drug-induced exon skipping preferentially affects shorter alternatively spliced regions with weaker BPs. Remarkably, structurally similar drugs display both common and differential effects on splicing regulation, SSA generally displaying stronger effects on intron retention, and Sudemycins more acute effects on exon skipping. Collectively, our results illustrate how splicing modulation is exquisitely sensitive to the sequence context of 3' splice sites and to small structural differences between drugs.Nature Publishing Group201820182017info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/34937http://dx.doi.org/10.1038/s41467-017-02007-zreponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésNature Communications. 2017 Dec 13;8(1):2100© The Author(s) 2017. 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/.http://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:recercat.cat:10230/349372026-05-29T05:05:01Z
dc.title.none.fl_str_mv Molecular basis of differential 3' splice site sensitivity to anti-tumor drugs targeting U2 snRNP
title Molecular basis of differential 3' splice site sensitivity to anti-tumor drugs targeting U2 snRNP
spellingShingle Molecular basis of differential 3' splice site sensitivity to anti-tumor drugs targeting U2 snRNP
Vigevani, Luisa, 1985-
Drug development
Mechanism of action
Rna splicing
Small molecules
title_short Molecular basis of differential 3' splice site sensitivity to anti-tumor drugs targeting U2 snRNP
title_full Molecular basis of differential 3' splice site sensitivity to anti-tumor drugs targeting U2 snRNP
title_fullStr Molecular basis of differential 3' splice site sensitivity to anti-tumor drugs targeting U2 snRNP
title_full_unstemmed Molecular basis of differential 3' splice site sensitivity to anti-tumor drugs targeting U2 snRNP
title_sort Molecular basis of differential 3' splice site sensitivity to anti-tumor drugs targeting U2 snRNP
dc.creator.none.fl_str_mv Vigevani, Luisa, 1985-
Gohr, André
Webb, Thomas R.
Irimia Martínez, Manuel
Valcárcel, J. (Juan)
author Vigevani, Luisa, 1985-
author_facet Vigevani, Luisa, 1985-
Gohr, André
Webb, Thomas R.
Irimia Martínez, Manuel
Valcárcel, J. (Juan)
author_role author
author2 Gohr, André
Webb, Thomas R.
Irimia Martínez, Manuel
Valcárcel, J. (Juan)
author2_role author
author
author
author
dc.subject.none.fl_str_mv Drug development
Mechanism of action
Rna splicing
Small molecules
topic Drug development
Mechanism of action
Rna splicing
Small molecules
description Several splicing-modulating compounds, including Sudemycins and Spliceostatin A, display anti-tumor properties. Combining transcriptome, bioinformatic and mutagenesis analyses, we delineate sequence determinants of the differential sensitivity of 3' splice sites to these drugs. Sequences 5' from the branch point (BP) region strongly influence drug sensitivity, with additional functional BPs reducing, and BP-like sequences allowing, drug responses. Drug-induced retained introns are typically shorter, displaying higher GC content and weaker polypyrimidine-tracts and BPs. Drug-induced exon skipping preferentially affects shorter alternatively spliced regions with weaker BPs. Remarkably, structurally similar drugs display both common and differential effects on splicing regulation, SSA generally displaying stronger effects on intron retention, and Sudemycins more acute effects on exon skipping. Collectively, our results illustrate how splicing modulation is exquisitely sensitive to the sequence context of 3' splice sites and to small structural differences between drugs.
publishDate 2017
dc.date.none.fl_str_mv 2017
2018
2018
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10230/34937
http://dx.doi.org/10.1038/s41467-017-02007-z
url http://hdl.handle.net/10230/34937
http://dx.doi.org/10.1038/s41467-017-02007-z
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Nature Communications. 2017 Dec 13;8(1):2100
dc.rights.none.fl_str_mv http://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Nature Publishing Group
publisher.none.fl_str_mv Nature Publishing Group
dc.source.none.fl_str_mv reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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