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Alternative Splicing, Apoptosis and Cancer: Targeting G-quadruplexes and splicing factors for novel therapies - 7 December 2021

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Speaker: Professor Cyril Dominguez, Institute of Structural and Chemical Biology, Department of Molecular and Cell Biology, University of Leicester

Host: Sasi Conte

Abstract: The Bcl-x gene produces two alternative isoforms that have antagonist functions: Bcl-xL is anti-apoptotic, while Bcl-xS is pro-apoptotic. In many cancer cells, the anti-apoptotic Bcl-xL isoform is upregulated. Our research aims at better understanding the regulation of Bcl-x alternative splicing and deriving small molecules that shift splicing towards the pro-apoptotic isoform.

Using a novel method, we have identified transient regulatory G-quadruplexes (G4) present in the Bcl-x pre-mRNA (1) and characterized small G4-binding molecules that regulate the alternative splicing of Bcl-x towards the pro-apoptotic isoform (2). We will present our recent work aiming at understanding how these molecules act on the pre-mRNA.

Bcl-x is regulated by the splicing factor Sam68, a member of the STAR family of proteins whose overexpression is associated with poor prognosis in various cancers.

We have unraveled the structural basis of dimerization and RNA recognition by Sam68 (3). Furthermore, we have demonstrated that Sam68 T33 and T317 are specifically phosphorylated by Cdk1 and that these phosphorylation events reduce Sam68 RNA binding ability and affect its cellular functions.

(1) Weldon et al, Nat. Chem. Biol., 13, 18-20 (2017)

(2) Weldon et al, Nucleic Acids Res., 46, 886-96 (2018)

(3) Feracci et al, Nat. Commun., 7, 10355 (2016)


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