PARPs and ADP-ribosyl hydrolases in cancer therapy: From drug targets to biomarkers

The PARP family of enzymes catalyzes ADP-ribosylation, a modification of macromolecules, and plays a crucial role in DNA damage repair. The landmark discovery that cancer cells deficient in homologous recombination repair are highly sensitive to PARP inhibitors has paved the way for the clinical success of multiple PARP inhibitors in the treatment of breast, ovarian, pancreatic, and prostate cancers. This clinical success has spurred interest in targeting additional regulators of ADP-ribosylation, with the ADP-ribosyl hydrolase PARG emerging as a promising therapeutic target. Pre-clinical studies have revealed that PARG inhibitors amplify and exploit replication-associated defects, offering a therapeutic window distinct from that of PARP inhibitors. This review provides an overview of the physiological functions of PARPs and PARG, examines the molecular and cellular effects of their inhibitors, and discusses their clinical applications. Finally, we explore the potential of other ADP-ribosylation regulators as novel cancer biomarkers.