Transient Poly(ADP-Ribose) Triggers FUS Condensation Hysteresis via a Prion-Like Mechanism

Area of Science:

• Cellular Biology
• Biochemistry
• Molecular Biology

Background:

• Hysteresis, or memory of transient stimuli, is observed in cellular signaling and intracellular organization.
• DNA repair foci are biomolecular condensates initiated by short-lived poly(ADP-ribose) (PAR).
• Proteins with prion-like domains (PrLDs), like Fused in Sarcoma (FUS), are recruited by PAR to form condensates that persist after PAR degradation.

Purpose of the Study:

• To elucidate the mechanism by which FUS transitions from PAR-dependent to PAR-independent condensation.
• To understand how intracellular organization exhibits hysteresis.

Main Methods:

• Investigated the conformational changes in FUS upon PAR binding.
• Characterized the role of FUS's C-terminal arginine-rich region and N-terminal PrLD in condensation.
• Utilized biophysical techniques to study protein-nucleic acid interactions and condensate stability.

Main Results:

• PAR binding induces a conformational switch in FUS, exposing its N-terminal PrLD.
• This conformational opening facilitates sustained, PAR-independent condensation through intermolecular interactions.
• FUS undergoes a regulated, nucleated conformational conversion, similar to prion formation.

Conclusions:

• A paradigm of nucleic acid-induced conformational memory underlies hysteresis in intracellular organization.
• This mechanism is crucial for understanding FUS condensate dynamics in cellular processes and disease.