Specific G-quadruplex ligands modulate the alternative splicing of Bcl-X

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dc.cclicenceCC-BY-NCen
dc.contributor.authorWeldon, Carikaen
dc.contributor.authorDacanay, J.G.en
dc.contributor.authorGokhale, V.en
dc.contributor.authorBoddupally, P.en
dc.contributor.authorBehm-Ansmant, Isabelleen
dc.contributor.authorBurley, Glenn A.en
dc.contributor.authorBranlant, Christianeen
dc.contributor.authorHurley, Laurence H.en
dc.contributor.authorDominguez, Cyrilen
dc.contributor.authorEperon, Ian C.en
dc.date.acceptance2017-10-26en
dc.date.accessioned2018-07-23T10:10:37Z
dc.date.available2018-07-23T10:10:37Z
dc.date.issued2018-01-25
dc.descriptionopen access articleen
dc.description.abstractSequences with the potential to form RNA G-quadruplexes (G4s) are common in mammalian introns, especially in the proximity of the 5′ splice site (5′SS). However, the difficulty of demonstrating that G4s form in pre-mRNA in functional conditions has meant that little is known about their effects or mechanisms of action. We have shown previously that two G4s form in Bcl-X pre-mRNA, one close to each of the two alternative 5′SS. If these G4s affect splicing but are in competition with other RNA structures or RNA binding proteins, then ligands that stabilize them would increase the proportion of Bcl-X pre-mRNA molecules in which either or both G4s had formed, shifting Bcl-X splicing. We show here that a restricted set of G4 ligands do affect splicing, that their activity and specificity are strongly dependent on their structures and that they act independently at the two splice sites. One of the ligands, the ellipticine GQC-05, antagonizes the major 5′SS that expresses the anti-apoptotic isoform of Bcl-X and activates the alternative 5′SS that expresses a pro-apoptotic isoform. We propose mechanisms that would account for these see-saw effects and suggest that these effects contribute to the ability of GQC-05 to induce apoptosis.en
dc.exception.reasonThe output was published as gold open accessen
dc.funderMedical Research Council Career Development Awarden
dc.funderSir Dudley Spurling Post Graduate Scholarship from the bank of N.T. Butterfield & Son Limiteden
dc.funderCentre National de la Recherche Scientifiqueen
dc.funderLorraine University; European Alternative Splicing Network of Excellenceen
dc.funderNational Foundation for Cancer Researchen
dc.funderNIHen
dc.identifier.citationWeldon, C., Dacanay, J.G., Gokhale, V. Boddupally, P., Behm-Ansmant, I., Burley, G.A., Branlant, C., Hurley, L.H., Dominguez, C., Eperon, I.C. (2018) Specific G-quadruplex ligands modulate the alternative splicing of Bcl-X. Nuclaic Acids Research, 46(2), pp.886-896.en
dc.identifier.doihttps://doi.org/10.1093/nar/gkx1122
dc.identifier.urihttp://hdl.handle.net/2086/16388
dc.language.isoenen
dc.projectidG1000526en
dc.projectidN/Aen
dc.projectidUMR 7365en
dc.projectidEURASNET, LSHG-CT-2005–518238en
dc.projectidVONHOFF-15–01en
dc.projectid5RO1CA177585–4en
dc.publisherOxford University Pressen
dc.titleSpecific G-quadruplex ligands modulate the alternative splicing of Bcl-Xen
dc.typeArticleen

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