Related Experiment Video
Updated: Jun 28, 2026
05:37
Single-Molecule Fluorescence Visualization of DNA Polymerase Dynamics at G-Quadruplexes
Published on: April 4, 2025
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, United States.
Nucleic Acids Research
|June 27, 2026
Summary
RNA G-quadruplexes (rG4s) can control the liquid-liquid phase separation (LLPS) of FUS proteins. These rG4 structures offer a way to reverse toxic FUS aggregation in neurodegenerative diseases.
Area of Science:
- Biochemistry
- Molecular Biology
- Neuroscience
Background:
- Fused in sarcoma (FUS) protein undergoes liquid-liquid phase separation (LLPS) for cellular functions.
- Aberrant FUS phase transitions are linked to toxic aggregation in neurodegenerative diseases.
- Short RNA oligonucleotides can reverse aberrant FUS LLPS, but their mechanisms are unclear.
Purpose of the Study:
- To identify structural determinants of RNA that modulate FUS LLPS.
- To explore RNA G-quadruplexes (rG4s) as regulators of FUS phase behavior.
- To develop RNA-based strategies for dissolving pathogenic FUS assemblies.
Main Methods:
- Investigated the effect of rG4 structure (length, stability) on FUS LLPS.
- Analyzed rG4 interactions with soluble and condensed FUS.
- Developed a bioinformatic pipeline to discover novel rG4 inhibitors.
Main Results:
- rG4s potently modulate FUS LLPS; activity depends on concentration, length, and stability.
- Increasing rG4 repeat number shifts activity from inhibition to nucleation.
- Stabilizing modifications enhance rG4 inhibitory function and ionic resilience.
- Short rG4s preferentially interact with soluble FUS, promoting dispersion.
- Discovered new rG4 inhibitors that reverse FUS LLPS and aggregation.
Conclusions:
- rG4s are tunable, chemically programmable regulators of protein phase behavior.
- Established a structure-function paradigm for RNA control of biomolecular condensates.
- rG4s provide a blueprint for RNA-based therapeutics against FUS aggregation.
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