Specific G-quadruplex ligands modulate the alternative splicing of Bcl-X.pdf (3.52 MB)
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Specific G-quadruplex ligands modulate the alternative splicing of Bcl-X.

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journal contribution
posted on 23.04.2018, 12:48 by Carika Weldon, Justine G Dacanay, V Gokhale, PVL Boddupally, I Behm-Ansmant, GA Burley, C Branlant, LH Hurley, Cyril Dominguez, Ian C. Eperon
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.

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Citation

Nucleic Acids Research, 2018, 46 (2), pp. 886-896

Author affiliation

/Organisation/COLLEGE OF LIFE SCIENCES/Biological Sciences/Molecular & Cell Biology

Version

VoR (Version of Record)

Published in

Nucleic Acids Research

Publisher

Oxford University Press

issn

0305-1048

eissn

1362-4962

Acceptance date

26/10/2017

Copyright date

2017

Available date

23/04/2018

Publisher version

https://academic.oup.com/nar/article/46/2/886/4634008

Language

en

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