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Updated: Jan 10, 2026
05:37
Single-Molecule Fluorescence Visualization of DNA Polymerase Dynamics at G-Quadruplexes
Published on: April 4, 2025
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RNA G-Quadruplexes Function as a Tunable Switch of FUS Phase Separation
Jenny L Carey1, Miyuki Hayashi1, Emily Welebob2
1Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Biorxiv : the Preprint Server for Biology
|November 24, 2025
Summary
RNA G-quadruplexes (rG4s) can control the phase separation of FUS proteins. Specific rG4 structures inhibit toxic FUS aggregation, offering a new therapeutic strategy for neurodegenerative diseases.
Area of Science:
- Biochemistry
- Molecular Biology
- Neuroscience
Background:
- FUS protein undergoes liquid-liquid phase separation (LLPS) for cellular functions.
- Aberrant FUS phase transitions are linked to neurodegenerative diseases.
- RNA oligonucleotides can reverse toxic FUS aggregation, but their mechanisms are unclear.
Purpose of the Study:
- To identify structural determinants of RNA that modulate FUS LLPS.
- To investigate RNA G-quadruplexes (rG4s) as regulators of FUS phase behavior.
- To develop RNA-based therapeutics for FUS-related disorders.
Main Methods:
- Investigated the effect of rG4 structure, concentration, length, and stability on FUS LLPS.
- Utilized a bioinformatic pipeline to discover novel rG4 inhibitors.
- Analyzed FUS-RNA interactions using biophysical techniques.
Main Results:
- Identified rG4s as potent modulators of FUS LLPS.
- Demonstrated that rG4 activity is tunable by length and stability, switching between inhibition and nucleation.
- Showed that stabilized rG4s inhibit FUS assembly and resist ionic disruption.
- Discovered that short rG4s preferentially interact with soluble FUS, promoting dispersion.
- Uncovered new rG4 inhibitors that reverse FUS LLPS and aggregation.
Conclusions:
- rG4s are chemically programmable regulators of protein phase behavior.
- RNA secondary structure dictates functional outcomes in protein condensates.
- rG4s offer a blueprint for RNA-based therapeutics targeting pathogenic FUS assemblies.
- Established a structure-function paradigm for RNA control of biomolecular condensates.
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