Vigevani, Luisa, 1985-Gohr, AndréWebb, Thomas R.Irimia Martínez, ManuelValcárcel, J. (Juan)2018-06-202018-06-202017Vigevani L, Gohr A, Webb T, Irimia M, Valcárcel J. Molecular basis of differential 3' splice site sensitivity to anti-tumor drugs targeting U2 snRNP. Nat Commun. 2017 Dec 13;8(1):2100. DOI: 10.1038/s41467-017-02007-z2041-1723http://hdl.handle.net/10230/34937Several 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.application/pdfeng© 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/.info:eu-repo/semantics/articlehttp://dx.doi.org/10.1038/s41467-017-02007-zDrug developmentMechanism of actionRna splicingSmall moleculesinfo:eu-repo/semantics/openAccess