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Nucleic Acids Res. 2018 Jan 25;46(2):886-896. doi: 10.1093/nar/gkx1122.

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

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Leicester Institute of Structural & Chemical Biology and Department of Molecular & Cell Biology, University of Leicester, Leicester LE1 7RH, UK.
College of Pharmacy and College of Pharmacy and BIO5 Institute, University of Arizona, Tucson, AZ 85721, USA.
Fluoroorganic Division, CSIR-Indian Institute of Chemical Technology, Hyderabad, Telangana 500 007, India.
IMoPA (Ingénierie Moléculaire et Physiopathologie Articulaire), UMR 7365 CNRS-UL, Biopôle de l'Université de Lorraine, 9 Avenue de la Forêt de Haye, 54505 Vandoeuvre-lès-Nancy, France.
Department of Pure and Applied Chemistry, University of Strathclyde, Glasgow G1 1XL, UK.
Arizona Cancer Center, University of Arizona, Tucson, AZ 85724, USA.


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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