Poly [ADP-ribose] polymerase 2 (PARP2) (PARP2)

Poly [ADP-ribose] polymerase 2 (PARP2) is a nuclear enzyme that functions as a critical sensor and mediator in the DNA damage response, particularly within the base excision repair (BER) pathway [1, 4]. It utilizes NAD+ as a substrate to catalyze the synthesis of poly(ADP-ribose) (PAR) chains on itself and other acceptor proteins, a process that facilitates the recruitment of downstream repair factors like XRCC1 and DNA polymerase beta [1, 5]. While PARP1 is the predominant PARP isoform, PARP2 has unique and essential roles in erythropoiesis, metabolic regulation via SIRT1, and the maintenance of telomere and centromere integrity [2, 5, 11]. In the context of oncology, PARP2 is a validated therapeutic target; most clinically approved PARP inhibitors, such as olaparib and niraparib, are dual inhibitors of PARP1 and PARP2 [6, 7]. These agents induce synthetic lethality in tumors with homologous recombination deficiencies, such as those harboring BRCA1 or BRCA2 mutations, by inhibiting catalytic activity and trapping PARP proteins on DNA [7, 12]. Notably, PARP2 inhibition is strongly associated with the hematologic toxicities observed in patients, leading to a shift in drug development toward PARP1-selective inhibitors to minimize side effects while maintaining anti-tumor efficacy [8, 9].

Other names

ADPRT2ADPRTL2ADPRTL3ARTD2pADPRT-2Poly [ADP-ribose] synthase 2

PARP inhibitors compete with NAD+ for the catalytic site of PARP2, inhibiting its enzymatic activity and preventing the PARylation of target proteins [7, 12]. Additionally, these drugs trap PARP2 on DNA at sites of damage, creating stable PARP-DNA complexes that block replication forks and lead to lethal double-strand breaks in cells with homologous recombination deficiencies [6, 9, 14].