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

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 m...

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Autores principales: Weldon, Carika, Dacanay, Justine G, Gokhale, Vijay, Boddupally, Peda Venkat L, Behm-Ansmant, Isabelle, Burley, Glenn A, Branlant, Christiane, Hurley, Laurence H, Dominguez, Cyril, Eperon, Ian C
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5778605/
https://www.ncbi.nlm.nih.gov/pubmed/29156002
http://dx.doi.org/10.1093/nar/gkx1122
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author Weldon, Carika
Dacanay, Justine G
Gokhale, Vijay
Boddupally, Peda Venkat L
Behm-Ansmant, Isabelle
Burley, Glenn A
Branlant, Christiane
Hurley, Laurence H
Dominguez, Cyril
Eperon, Ian C
author_facet Weldon, Carika
Dacanay, Justine G
Gokhale, Vijay
Boddupally, Peda Venkat L
Behm-Ansmant, Isabelle
Burley, Glenn A
Branlant, Christiane
Hurley, Laurence H
Dominguez, Cyril
Eperon, Ian C
author_sort Weldon, Carika
collection PubMed
description 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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spelling pubmed-57786052018-01-30 Specific G-quadruplex ligands modulate the alternative splicing of Bcl-X Weldon, Carika Dacanay, Justine G Gokhale, Vijay Boddupally, Peda Venkat L Behm-Ansmant, Isabelle Burley, Glenn A Branlant, Christiane Hurley, Laurence H Dominguez, Cyril Eperon, Ian C Nucleic Acids Res RNA and RNA-protein complexes 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. Oxford University Press 2018-01-25 2017-11-16 /pmc/articles/PMC5778605/ /pubmed/29156002 http://dx.doi.org/10.1093/nar/gkx1122 Text en © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle RNA and RNA-protein complexes
Weldon, Carika
Dacanay, Justine G
Gokhale, Vijay
Boddupally, Peda Venkat L
Behm-Ansmant, Isabelle
Burley, Glenn A
Branlant, Christiane
Hurley, Laurence H
Dominguez, Cyril
Eperon, Ian C
Specific G-quadruplex ligands modulate the alternative splicing of Bcl-X
title Specific G-quadruplex ligands modulate the alternative splicing of Bcl-X
title_full Specific G-quadruplex ligands modulate the alternative splicing of Bcl-X
title_fullStr Specific G-quadruplex ligands modulate the alternative splicing of Bcl-X
title_full_unstemmed Specific G-quadruplex ligands modulate the alternative splicing of Bcl-X
title_short Specific G-quadruplex ligands modulate the alternative splicing of Bcl-X
title_sort specific g-quadruplex ligands modulate the alternative splicing of bcl-x
topic RNA and RNA-protein complexes
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5778605/
https://www.ncbi.nlm.nih.gov/pubmed/29156002
http://dx.doi.org/10.1093/nar/gkx1122
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