PARG

Class

small molecule

Notes

original target text: PARG inhibitor

PARG (poly(ADP-ribose) glycohydrolase) is an enzyme that reverses a specific form of protein modification called PARylation. When DNA is damaged, PARP enzymes attach chains of poly(ADP-ribose) (PAR) onto proteins at the damage site, acting as a signal that recruits repair machinery. PARG normally removes these PAR chains once repair is underway, allowing the process to reset and continue. Blocking PARG causes PAR chains to accumulate and persist, which disrupts the normal cycle of DNA damage signaling and repair. This is conceptually related to, but mechanistically distinct from, inhibiting PARP itself. In cancers that already have impaired DNA repair capacity—such as tumors with defects in homologous recombination, a major DNA repair pathway—cells are more dependent on PARylation-based repair processes to survive replication stress. Disabling PARG in this context can push such cells toward a degree of genomic instability that is incompatible with survival, a concept known as synthetic lethality. Because this vulnerability is more pronounced in DNA-repair-deficient tumor cells than in normal tissue, PARG inhibition is being explored as a strategy to selectively harm cancer cells while sparing healthy cells, particularly in tumor types already associated with defective repair pathways.