Poly [ADP-ribose] polymerase 1/2 (PARP1/2)

Poly [ADP-ribose] polymerase 1 (PARP1) and Poly [ADP-ribose] polymerase 2 (PARP2) are closely related enzymes belonging to the PARP family and the diphtheria-toxin-like ADP ribosyltransferase (ART) family. They catalyze poly(ADP-ribosyl)ation (PARylation), a post-translational modification transferring ADP-ribose units from NAD+ to target proteins. PARP1 is larger with six domains including zinc fingers, BRCT, WGR, and catalytic domains, primarily binding DNA via zinc fingers and WGR. PARP2 is simpler, with an intrinsically disordered N-terminus, WGR domain for DNA binding, and a catalytic domain similar to PARP1. PARP1 accounts for the majority of cellular PAR formation under DNA damage, while PARP2 contributes the remainder with lower substrate affinity. Both are crucial for DNA damage response and base-excision repair (BER), interacting with repair factors like XRCC1, DNA polymerase β, and DNA ligase III. They also regulate chromatin structure; PARP1 modifies histones to decompact chromatin, and the PARP2-HPF1 complex can bridge nucleosomes. Their involvement in DNA repair makes them therapeutic targets, especially in cancers with homologous recombination deficiencies like BRCA mutations. They are implicated in cancer, inflammation, metabolic disorders, and oxidative stress. PARP inhibitors (PARPi) are developed therapies, classified into types like Type I which promote PARP1 retention on DNA. Recent findings highlight HPF1 as a key factor redirecting PARylation to serine residues and enabling histone transPARylation, contributing a catalytic residue. The cryo-EM structure of PARP2/HPF1 complex with a nucleosome has revealed insights into their interaction with chromatin.

Other names

PARP1PARP2Poly [ADP-ribose] polymerase 1Poly [ADP-ribose] polymerase 2Poly(ADP-ribose) polymerase 1Poly(ADP-ribose) polymerase 2

PARP inhibitors (PARPi) are therapeutic agents targeting PARP1 and PARP2 due to their crucial roles in DNA repair mechanisms. Specific types, such as Type I inhibitors, promote allosteric retention of PARP1 on DNA.