Bcl-X pre-mRNA G-quadruplex (Bcl-X rG4)

The Bcl-X pre-mRNA G-quadruplex is a non-canonical secondary structure formed within the guanine-rich regions of the BCL2L1 (Bcl-X) pre-messenger RNA (Nucleic Acids Res. 2018;46:886–896). This structure plays a critical role in the alternative splicing of the Bcl-X gene, which produces two isoforms with antagonistic functions: the anti-apoptotic Bcl-xL and the pro-apoptotic Bcl-xS (Nucleic Acids Res. 2023;51(20):11239-11257). Specifically, G-quadruplexes located near the alternative 5' splice sites, such as GQ-2 and GQ-5, regulate the accessibility of these sites to the splicing machinery and the recruitment of splicing factors like RBM25 (Front. Mol. Biosci. 2022;9:956134). In many cancers, the balance is shifted toward Bcl-xL, contributing to tumor survival and chemoresistance. Small molecule ligands like GQC-05 and PhenDC3 that stabilize these G-quadruplexes can redirect splicing to favor the Bcl-xS isoform, thereby inducing apoptosis in cancer cells (Nucleic Acids Res. 2018;46:886–896). Consequently, the Bcl-X pre-mRNA G-quadruplex is an emerging therapeutic target for oncology and other diseases characterized by aberrant splicing, such as diabetes and cardiac disorders. Research indicates that targeting these structures allows for precise modulation of protein isoforms, offering a novel approach to re-sensitize resistant tumors to chemotherapy.

Other names

Bcl-X RNA G-quadruplexBCL2L1 pre-mRNA G-quadruplexGQ-2GQ-5Bcl-x G-quadruplex

Stabilization of the G-quadruplex structure within the Bcl-X pre-mRNA modulates the selection of alternative 5' splice sites, shifting the splicing ratio from the anti-apoptotic Bcl-xL isoform to the pro-apoptotic Bcl-xS isoform by altering splice site accessibility or recruiting splicing factors like RBM25.