Poly(ADP-ribose) polymerase 1 (PARP1) (PARP1)

Poly(ADP-ribose) polymerase 1 (PARP1) is the primary enzyme in the PARP family, accounting for 80-90% of cellular poly(ADP-ribose) synthesis, and plays a central role in DNA damage repair by detecting single-strand breaks and facilitating base excision repair through ADP-ribosylation of histones and repair factors. Upon DNA damage, PARP1's zinc finger domains bind damaged sites, triggering allosteric activation of its catalytic domain to transfer ADP-ribose from NAD+ onto target proteins, promoting chromatin relaxation and recruitment of repair machinery. PARP1 also contributes to genomic stability, transcription regulation, and apoptosis; excessive activation depletes cellular NAD+ and ATP, leading to programmed necrosis (parthanatos). In disease, PARP1 hyperactivation exacerbates ischemia-reperfusion injury and neurodegeneration, while its inhibition exploits synthetic lethality in cancers with BRCA1/2 mutations or homologous recombination defects, where unrepaired DNA damage causes cell death. PARP inhibitors like olaparib trap PARP1 on DNA, preventing repair and amplifying cytotoxicity in HR-deficient tumors, establishing PARP1 as a validated oncology target.

Other names

PARPPAR polymerizing enzymeADP-ribosyltransferaseADPRT

Inhibition of DNA repair via PARP trapping on DNA, Synthetic lethality in BRCA-mutated cancers, Blockade of poly(ADP-ribose) synthesis