Document Type

Article

Publication Date

6-22-2026

Comments

This article is the author’s final published version in Nucleic Acids Research, Volume 54, Issue 12, 2026, Article number gkag594.

The published version is available at https://doi.org/10.1093/nar/gkag594. Copyright © The Author(s) 2026.

 

Abstract

Fused in sarcoma (FUS) undergoes liquid-liquid phase separation (LLPS) to support essential cellular functions, but aberrant phase transitions promote toxic aggregation in neurodegenerative disease. Short RNA oligonucleotides can reverse this behavior, yet the structural determinants that govern RNA activity remain poorly defined. Here, we identify RNA G-quadruplexes (rG4s) as tunable structural motifs that potently modulate FUS LLPS. rG4 activity depends on its concentration and is modulated by rG4 length and stability: increasing repeat number switches rG4s from inhibitor to nucleator of FUS assembly, whereas chemical modifications that stabilize rG4 enhance inhibitory function and render these activities resilient to ionic perturbation. Although short rG4s interact with both soluble and condensed FUS, they preferentially engage the soluble pool, likely shifting the equilibrium toward dispersion. Leveraging these mechanistic insights, we developed a bioinformatic pipeline that uncovered more rG4 inhibitors that robustly reverse FUS LLPS and aggregation. Our findings establish rG4s as chemically programmable regulators of protein phase behavior and provide a blueprint for engineering RNA-based therapeutics that dissolve pathogenic FUS assemblies. More broadly, this work directly links RNA secondary structure to distinct functional outcomes in phase behavior, establishing a structure-function paradigm for RNA control of condensates, demonstrating implications in both fundamental biology and therapeutic development.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.

Additional Files
Supplemental File.pdf (7007 kB)

PubMed ID

42363764

Language

English

Download

Share

COinS
 
 

To view the content in your browser, please download Adobe Reader or, alternately,
you may Download the file to your hard drive.

NOTE: The latest versions of Adobe Reader do not support viewing PDF files within Firefox on Mac OS and if you are using a modern (Intel) Mac, there is no official plugin for viewing PDF files within the browser window.