PARPs

PARPs, or poly(ADP-ribose) polymerases, are a family of enzymes that catalyze the transfer of ADP-ribose units from NAD+ to target proteins, forming poly(ADP-ribose) chains. The best studied members are PARP1 and PARP2, which rapidly respond to DNA damage. Upon binding to DNA strand breaks, PARP1 undergoes autoPARylation and recruits base excision repair factors, chromatin remodelers, and other DNA damage response proteins to facilitate repair.

Inhibiting PARP activity disrupts DNA repair and can lead to cell death, especially in cells deficient in homologous recombination repair, such as BRCA1/2-mutant cancers. PARP inhibitors not only block catalytic activity but can also trap PARP enzymes on DNA, increasing replication stress. This synthetic lethality has made PARP inhibitors a targeted approach in oncology, particularly for tumors with BRCA mutations or other HR defects.

The PARP family comprises multiple members with diverse roles. PARP1, PARP2, and PARP3 contribute to single-strand break repair and chromatin regulation, while tankyrases (PARP5A/TNKS and PARP5B/TNKS2) participate in Wnt signaling, telomere maintenance, and centrosome function. Clinically used PARP inhibitors include olaparib, niraparib, rucaparib, and talazoparib. They are approved for BRCA1/2-mutated ovarian, breast, pancreatic, and prostate cancers and are explored in combination with chemotherapy, radiation, or immunotherapy.

Resistance to PARP inhibitors can arise from restoration of homologous recombination, BRCA1/2 reversion mutations, replication fork protection, or reduced PARP trapping. Common adverse effects include anemia, thrombocytopenia, nausea, and fatigue. Ongoing research investigates broader biomarker strategies, resistance mechanisms, and non-cancer roles of PARP enzymes in inflammation and aging.