Poly(ADP-ribose) polymerase 1 and Poly(ADP-ribose) polymerase 2 (PARP1 and PARP2)

Poly(ADP-ribose) polymerase 1 (PARP1) and poly(ADP-ribose) polymerase 2 (PARP2) are nuclear enzymes primarily involved in the detection and repair of DNA single-strand breaks through poly(ADP-ribosyl)ation (PARylation) of nuclear proteins, using NAD+ as a substrate. PARP1 accounts for approximately 90% of overall PARP activity while PARP2 provides the remainder. Both proteins act as critical regulators of genome maintenance, chromatin remodeling, transcription, apoptosis, and cellular responses to DNA damage. PARP1 and PARP2 are considered major targets for cancer therapy, particularly for tumors with homologous recombination defects, such as those harboring BRCA1/2 mutations. Clinically approved PARP inhibitors leverage these vulnerabilities to induce synthetic lethality. While the canonical roles of both proteins show some overlap, they differ in domain structure and substrate preference, with PARP1 containing multiple zinc finger domains for DNA binding, and PARP2 with a distinct WGR domain. Together, they cooperate and have both redundant and unique roles in cell homeostasis and pathology, emphasizing their central position in DNA repair signaling and as established therapeutic targets in oncology[2][3][4][6][8].

Other names

ADPRT 1 (for PARP1)ADPRT 2 (for PARP2)PARP-1PARP-2Poly(ADP-ribose) synthetase 1/2

Inhibitors bind to the NAD+ binding site of PARP1/2, blocking poly(ADP-ribosyl)ation of protein targets and inhibiting repair of single-strand DNA breaks[6][2][8]. “PARP trapping”: Inhibitors not only block catalytic activity but also promote persistence of PARP1/2 on damaged chromatin, which is cytotoxic in BRCA1/2-mutant cells[2][6][4]. Induction of synthetic lethality in homologous recombination-deficient cancer cells (e.g., BRCA1/2-mutants)[8].