Poly (ADP-ribose) polymerase family catalytic domains (PARP catalytic domains)

The Poly (ADP-ribose) polymerase (PARP) family, also known as the ADP-ribosyltransferase D-type (ARTD) family, consists of 17 members in humans that share a conserved catalytic domain responsible for transferring ADP-ribose units from NAD+ to target proteins [1, 2]. While PARP1 and PARP2 are the most prominent therapeutic targets due to their critical roles in DNA repair and the clinical success of inhibitors like Olaparib in BRCA-mutant cancers, the "other" members of the family possess distinct and diverse biological roles [3]. These include PARP3, which participates in DNA double-strand break repair, and the Tankyrases (PARP5a/b), which regulate Wnt signaling and telomere length [2, 4]. Many other family members, such as PARP7, PARP10, and PARP14, function as mono-ADP-ribosyltransferases (mARTs) and are involved in the innate immune response, stress signaling, and transcriptional regulation [4, 5]. Selective inhibitors targeting these "other" catalytic domains are currently in development, such as the PARP7 inhibitor RBN-2397, which aims to enhance anti-tumor immunity by modulating the type I interferon response [5]. Understanding the selectivity of PARP inhibitors across these various catalytic domains is crucial for both maximizing therapeutic efficacy and minimizing off-target toxicities associated with broad-spectrum inhibition [3, 4].

Other names

ARTD family catalytic domainsPoly [ADP-ribose] polymerase familyNon-PARP1/2 PARP membersMono-ADP-ribosyltransferase domains

Competitive inhibition of the NAD+ binding site within the catalytic domain, preventing the transfer of ADP-ribose units to substrate proteins [2, 4].