G-quadruplex structural motifs modulate protein–RNA interactions within the transcriptome

RNA secondary structures, including G-quadruplexes (G4s), have emerged as vital players in protein-RNA interactions. The RNA-binding protein Fused in Sarcoma (FUS), which is strongly implicated in both neurodegenerative disease and cancer, is known to interact with RNA molecules through a variety of GU-rich sequences. However, a definitive consensus motif for FUS-RNA recognition and binding has not yet been determined. Here, we hypothesize that G4 structures, which are inherently G-rich, may play a key role in FUS binding. We examine the role of G4s in FUS-RNA binding by developing an RNA immunoprecipitation sequencing (RIP-seq) protocol under G4-stabilizing and non-stabilizing conditions. We find that G4s regulate the binding of FUS to target RNAs, providing new information on protein-RNA binding motifs, while reinforcing the importance of RNA secondary structures as pivotal regulators of protein interactions. These insights advance our understanding of FUS-RNA binding dynamics and future potential for identifying new therapeutic targets for neurodegenerative disease and other FUS-related pathologies.