Specific G-quadruplex ligands modulate the alternative splicing of Bcl-X
Dacanay, Justine G
Boddupally, Peda Venkat L
Burley, Glenn A
Hurley, Laurence H
Eperon, Ian C
AffiliationUniv Arizona, Arizona Canc Ctr
Univ Arizona, Coll Pharm
Univ Arizona, Inst BIO5
MetadataShow full item record
PublisherOXFORD UNIV PRESS
CitationSpecific G-quadruplex ligands modulate the alternative splicing of Bcl-X 2018, 46 (2):886 Nucleic Acids Research
JournalNucleic Acids Research
Rights© The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research. This is an Open Access article distributed under the terms of the Creative Commons Attribution License.
Collection InformationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at firstname.lastname@example.org.
AbstractSequences 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 ormechanisms 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 premRNA 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.
NoteOpen access journal.
VersionFinal published version
SponsorsMedical Research Council Career Development Award [G1000526]; bank of N.T. Butterfield Son Limited; Centre National de la Recherche Scientifique [UMR 7365]; Lorraine University; European Alternative Splicing Network of Excellence [EURASNET] [LSHG-CT-2005-518238]; National Foundation for Cancer Research [VONHOFF-15-01]; NIH [5RO1CA177585-4]; University of Leicester
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