Functional Role of ADP-Ribosyl-Acceptor Hydrolase 3 in poly(ADPRibose) Polymerase-1 Response to Oxidative Stress

Abstract

Poly-ADP-ribosylation has been proposed to be a reversible protein modification, participating in diverse cellular functions including DNA repair, chromatin remodeling, genetic stability, mitosis, and cell death. Poly-ADP-ribosylation is initiated by the transfer of the ADP-ribose moiety of NAD+ primarily to the carboxyl groups of glutamate and aspartate and amino group of lysine residues in target proteins, followed by elongation of poly(ADP-ribose) (PAR) chains via α-O-glycosidic (C-1″-C-2′) ribose-ribose bonds. PAR consists of polymers of ADP-ribose (up to 200 units) with branching via α-O-glycosidic (C-1‴-C-2″) ribose-ribose bonds. Further, the pyrophosphate group of each ADP-ribose has two negative charges. Therefore, in proteins modified by PAR, a complex structure with negative charges may lead to dynamic changes of functions. PAR formation is catalyzed by poly(ADP-ribose) polymerases (PARPs) and terminated by several types of enzymes with PAR-degrading activities; poly(ADP-ribose) glycohydrolase (PARG), ADP-ribosyl-acceptor hydrolase (ARH) 3, ARH1, and macrodomain-containing proteins. PARG has been thought to be primarily responsible for PAR degradation. In 2006, ARH3 was cloned and identified as another type of PAR-degrading protein. Although PAR-degrading activity of ARH3 is less than that of PARG, different mechanisms of PAR recognition and the cellular localization of ARH3 appear to be responsible for unique cellular roles of ARH3 involving PAR. In the present review, we focused on our findings regarding structure, biological properties, and cellular functions of ARH3. In addition, we describe the current knowledge of poly-ADP-ribosylation and cell death pathways regulated PARP1, PARG, and ARH3.

Structure–function analyses reveal the mechanism of the ARH3-dependent hydrolysis of ADP-ribosylation

“…In addition to ADP-ribosylation, hydrolyzation of ADP-ribose also plays key roles in numerous biological processes (9,(15)(16)(17). In particular, ADPR hydrolyzation has been shown to participate in DNA damage repair (18,19). To date, more than 10 ADP-ribose hydrolases have been identified (18,20).…”

(ADP-ribosyl)hydrolases: structure, function, and biology

“…In vitro studies with all known (ADP-ribosyl)hydrolases indicate that for this function no backup pathway exists in mammalian cells ). In addition, hydrolysis of PAR chains as well as OAADPR has been reported for ARH3 Kasamatsu et al 2011;Mashimo and Moss 2016;Fontana et al 2017), but in this case, alternative hydrolases exist in the cells. PAR-removing activity of ARH3 has been linked to the regulation of parthanatos, a special type of apoptosis (Mashimo et al 2013;Dawson et al 2017;Robinson et al 2019).…”

Fused in Sarcoma (FUS) in DNA Repair: Tango with Poly(ADP-ribose) Polymerase 1 and Compartmentalisation of Damaged DNA

“…Protein PARylation is a reversible process mainly due to poly(ADP-ribose) glycohydrolase (PARG) activity and ADP-ribosyl-acceptor hydrolases 3 (ARH3), which catalyse the cleavage between ADP-ribose structural units at the terminal position and inside the polymer, thereby releasing ADP-ribose or oligo(ADP-ribose), respectively [ 98 , 99 ]. Thus, the action of PAR-degrading enzymes makes protein PARylation a dynamic and reversible post-translational modification and plays an important role in the regulation of DNA repair [ 98 , 99 , 100 ]. Protein PARylation, PAR length and formation of protein-free PAR molecules all contribute to the regulation of DNA repair, in particular, through the binding of proteins to PAR or their PARylation [ 16 , 21 , 25 , 100 ].…”