CBE Colloquia  - Targeting PARP Biology Beyond Cancer: Biomolecular Condensates, Infection, and Neurodegeneration

ADP-ribosylation, a reversible, nucleotide-like post-translational modification written by PARP enzymes, regulates gene expression, stress responses, and the formation of biomolecular condensates. While PARP inhibitors are approved for cancers with DNA-repair deficiencies (e.g. BRCA mutations), our work shows that ADP-ribosylation functions far beyond DNA repair, with key roles in cytoplasmic RNA metabolism, viral infection, and neurodegeneration. Using single-molecule assays, live-cell imaging, and quantitative proteomics developed in our lab, we find that poly(ADP-ribose) (PAR) potently - even at substoichiometric levels - triggers protein condensation in vitro and enriches membraneless assemblies in cells, including stress granules and DNA-repair foci. Stress granules, which sequester translation factors, are actively targeted by RNA viruses such as coronaviruses and alphaviruses; these pandemic-causing pathogens encode ADP-ribose–removing enzymes (viral macrodom! ains) that disassemble granules and redirect translation toward viral protein synthesis. Together, these findings position ADP-ribosylation as a targetable pathway beyond oncology - opening strategies to tune PARP activity, inhibit viral hydrolases, and modulate PAR-dependent condensates with implications for infection and neurodegenerative disease.