Advantages and Challenges of G‑Quadruplexes in Regulating Alternative Splicing

Area of Science:

• Molecular Biology
• Genetics
• Biochemistry

Background:

• Alternative splicing (AS) significantly expands proteomic diversity in eukaryotes.
• RNA secondary structures, particularly G-quadruplexes (G4s), are emerging as key regulators of AS.
• G4s are stable four-stranded structures formed by guanine-rich sequences.

Purpose of the Study:

• To review the role of RNA G-quadruplexes in alternative splicing.
• To explore G4 sequence features, genomic distribution, and interactions with RNA-binding proteins.
• To discuss the therapeutic potential of modulating G4 structures for disease treatment.

Main Methods:

• Genomic analyses to study G4 motif distribution near splice sites.
• Biochemical studies to investigate G4 interactions with RNA-binding proteins.
• Chemical biology approaches using small molecules to modulate G4 stability.

Main Results:

• G4-forming motifs show strand-specific enrichment near splice sites, suggesting conserved regulatory roles.
• RNA-binding proteins interact with G4s and single-stranded G-tracts to influence splicing.
• Small molecules targeting G4s can alter splicing patterns.

Conclusions:

• RNA G4s are dynamic regulators within the splicing network.
• G4 structures represent druggable targets for therapeutic intervention.
• Modulating G4s offers promising avenues for treating cancer and neurodegenerative diseases.