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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...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2018
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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. |
format | Online Article Text |
id | pubmed-5778605 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
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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