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

10 Citations (Scopus)

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.
LanguageEnglish
Number of pages11
JournalNucleic Acids Research
DOIs
Publication statusPublished - 16 Nov 2017

Fingerprint

G-Quadruplexes
RNA Splice Sites
Alternative Splicing
Ligands
RNA Precursors
ellipticine
Protein Isoforms
RNA-Binding Proteins
Introns
RNA
Apoptosis

Keywords

  • RNA G-quadruplexes
  • splicing
  • apoptosis

Cite this

Weldon, C., Dacanay, J. G., Gokhale, V., Boddupally, P. V. L., Behm-Ansmant, I., Burley, G. A., ... Eperon, I. C. (2017). Specific G-quadruplex ligands modulate the alternative splicing of Bcl-X. Nucleic Acids Research. https://doi.org/10.1093/nar/gkx1122
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. In: Nucleic Acids Research. 2017.
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Weldon, C, Dacanay, JG, Gokhale, V, Boddupally, PVL, Behm-Ansmant, I, Burley, GA, Branlant, C, Hurley, LH, Dominguez, C & Eperon, IC 2017, 'Specific G-quadruplex ligands modulate the alternative splicing of Bcl-X' Nucleic Acids Research. https://doi.org/10.1093/nar/gkx1122

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.

In: Nucleic Acids Research, 16.11.2017.

Research output: Contribution to journalArticle

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T1 - Specific G-quadruplex ligands modulate the alternative splicing of Bcl-X

AU - Weldon, Carika

AU - Dacanay, Justine G.

AU - Gokhale, Vijay

AU - Boddupally, Peda Venkat L.

AU - Behm-Ansmant, Isabelle

AU - Burley, Glenn A.

AU - Branlant, Christiane

AU - Hurley, Laurence H.

AU - Dominguez, Cyril

AU - Eperon, Ian C.

PY - 2017/11/16

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N2 - 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.

AB - 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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DO - 10.1093/nar/gkx1122

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T2 - Nucleic Acids Research

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