Regulation of Biomolecular Condensates by Poly(ADP-ribose)

Biomolecular condensates are reversible compartments that form through a process called phase separation. Post-translational modifications like ADP-ribosylation can nucleate the formation of these condensates by accelerating the self-association of proteins. Poly(ADP-ribose) (PAR) chains are remarkably transient modifications with turnover rates on the order of minutes, yet they can be required for the formation of granules in response to oxidative stress, DNA damage, and other stimuli. Moreover, accumulation of PAR is linked with adverse phase transitions in neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. In this review, we provide a primer on how PAR is synthesized and regulated, the diverse structures and chemistries of ADP-ribosylation modifications, and protein-PAR interactions. We review substantial progress in recent efforts to determine the molecular mechanism of PAR-mediated phase separation, and we further delineate how inhibitors of PAR polymerases may be effective treatments for neurodegenerative pathologies. Finally, we highlight the need for rigorous biochemical interrogation of ADP-ribosylation in vivo and in vitro to clarify the exact pathway from PARylation to condensate formation.

Automated summary

Biomolecular condensates are reversible compartments formed through phase separation, which can be nucleated by post-translational modifications like ADP-ribosylation. Poly(ADP-ribose) (PAR) chains, transient modifications with short turnover rates, play a crucial role in granule formation and are associated with neurodegenerative diseases. This review explores the synthesis, regulation, structure, chemistry, and protein interactions of PAR, as well as recent progress in understanding its role in phase separation and potential as a target for neurodegenerative disease treatments.