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- W2267967214 abstract "The Bcl-2 family of proteins are the primary regulators of the intrinsic apoptoticpathway, with anti-apoptotic members up regulated in cancer. Bcl-X is of particularinterest, as it can be alternatively spliced to yield antagonistic proteins, the proapoptoticBcl-XS and the anti-apoptotic Bcl-XL. Heterogeneous ribonuclearprotein(hnRNP) F/H, which binds to G-tract RNA, was shown to shift splicing in favour of theXS 5’ss (Garneau et al., 2005). G-tracts can form G-quadruplexes (G4s), which havebeen implicated to effect various stages of RNA processing, including splicing.Structural studies of hnRNP F/H revealed that it prefers to bind single stranded G-tractRNA (Dominguez et al., 2010) and competes with G4 formation (Samatanga et al.,2013). It was proposed that G4s may also form within the Bcl-X pre-mRNA that willalter 5’ss selection.In this study, two main questions were asked: (1) Is the Bcl-X pre-mRNA capable offorming any G4s (2) if so, do these G4s alter the 5’ss selection. Once a betterunderstanding of 5’ss selection in Bcl-X was attained, a novel non-intrusive method wasdeveloped that identified putative G4s regions in the presence of competing secondarystructures. Three main regions were highlighted for further investigation. By screeningover 30 G4 ligands for their effect on 5’ss selection in Bcl-X, it was revealed that G4ligands not only cause a shift to favour the pro-apoptotic site, but that such an effect isrestricted to certain structural classes of G4 ligands. By investigating the mechanism ofaction of the best G4 ligand from the screen, GQC-05, two independent non-canonicalG4s were found to be stabilized by GQC-05 owing to its dual effect on 5’ss selection.This not only expands the range of potential G4 forming sequences in RNA but alsooffers a new therapeutic strategy for alternative splicing regulation of apoptosis." @default.
- W2267967214 created "2016-06-24" @default.
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- W2267967214 date "2015-10-01" @default.
- W2267967214 modified "2023-09-26" @default.
- W2267967214 title "Regulation of Bcl-X splicing by G-quadruplexes enables regulation by G-quadruplex ligands to favour apoptosis" @default.
- W2267967214 hasPublicationYear "2015" @default.
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