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

Carika Weldon, Justine G. Dacanay, Vijay Gokhale, Peda Venkat L. Boddupally, Isabelle Behm-Ansmant, Glenn A. Burley, Christiane Branlant, Laurence H. Hurley, Cyril Dominguez, Ian C. Eperon

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

Sequences 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.

Original languageEnglish (US)
Pages (from-to)886-896
Number of pages11
JournalNucleic acids research
Volume46
Issue number2
DOIs
StatePublished - Jan 25 2018

ASJC Scopus subject areas

  • Genetics

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    Weldon, C., Dacanay, J. G., Gokhale, V., Boddupally, P. V. L., 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. Nucleic acids research, 46(2), 886-896. https://doi.org/10.1093/nar/gkx1122