Poly [ADP-ribose] polymerase (PARP)

The Poly [ADP-ribose] polymerase (PARP) family of enzymes, primarily PARP-1 and PARP-2, are essential sensors of DNA damage that facilitate the repair of single-strand breaks (SSBs) through the base excision repair pathway (UniProt P09874). Upon binding to damaged DNA, PARP uses nicotinamide adenine dinucleotide (NAD+) to synthesize and transfer poly(ADP-ribose) (PAR) chains onto itself and other nuclear proteins, a process that recruits repair factors (PubMed: 28102299). In oncology, PARP is a major therapeutic target due to the principle of synthetic lethality; cells with deficient homologous recombination (HR) repair, such as those with BRCA1 or BRCA2 mutations, are hypersensitive to PARP inhibition (StatPearls: NBK547716). PARP inhibitors work by blocking the enzyme's catalytic activity and by trapping the enzyme on DNA, which prevents the progression of replication forks and induces lethal double-strand breaks (PubMed: 22508508). Beyond cancer, PARP activation is linked to inflammatory and neurodegenerative processes through its role in regulating gene expression and cell death pathways like parthanatos (PubMed: 15123771). Clinically, these inhibitors are approved for various malignancies, including ovarian, breast, prostate, and pancreatic cancers, though resistance and hematologic toxicities remain significant clinical hurdles (NIH: PDQ Cancer Information).

Other names

Poly(ADP-ribose) synthetasePoly(ADP-ribose) transferaseADP-ribosyltransferase Diphtheria toxin-likeARTDPARP family

Inhibition of the catalytic activity of PARP enzymes and trapping of PARP proteins on DNA at sites of single-strand breaks, leading to the formation of double-strand breaks that cannot be repaired in homologous recombination-deficient cells.