ADP-ribosyl-acceptor hydrolase 3 regulates poly (ADP-ribose) degradation and cell death during oxidative stress

Abstract

Poly (ADP ribose) (PAR) formation catalyzed by PAR polymerase 1 in response to genotoxic stress mediates cell death due to necrosis and apoptosis. PAR glycohydrolase (PARG) has been thought to be the only enzyme responsible for hydrolysis of PAR in vivo. However, we show an alternative PAR-degradation pathway, resulting from action of ADP ribosyl-acceptor hydrolase (ARH) 3. PARG and ARH3, acting in tandem, regulate nuclear and cytoplasmic PAR degradation following hydrogen peroxide (H 2 O 2 ) exposure. PAR is responsible for induction of parthanatos, a mechanism for caspaseindependent cell death, triggered by apoptosis-inducing factor (AIF) release from mitochondria and its translocation to the nucleus, where it initiates DNA cleavage. PARG, by generating protein-free PAR from poly-ADP ribosylated protein, makes PAR translocation possible. A protective effect of ARH3 results from its lowering of PAR levels in the nucleus and the cytoplasm, thereby preventing release of AIF from mitochondria and its accumulation in the nucleus. Thus, PARG release of PAR attached to nuclear proteins, followed by ARH3 cleavage of PAR, is essential in regulating PAR-dependent AIF release from mitochondria and parthanatos.posttranslational modification | cytotoxicity P oly-ADP ribosylation is a reversible posttranslational modification of proteins, which results from the covalent attachment of branched polymers of ADP ribose moieties to amino acid residues of target proteins, in a reaction catalyzed by poly (ADP ribose) polymerases (PARP) (1-3). PARP1, a well-characterized member of the PARP family, is a nuclear protein that acts as a molecular sensor of DNA-strand breaks. Upon binding to sites of single-strand DNA breaks, PARP1 catalyzes the formation of a branched, long poly (ADP ribose) (PAR) chain attached to glutamate or aspartate residues of acceptor proteins including histones, DNA polymerases, topoisomerases, DNA ligase-2, transcription factors, and PARP1 itself (4-7). Poly-ADP ribosylation of these acceptor proteins alters their physical and biological properties, leading to DNA repair and the maintenance of genomic stability. In contrast, PARP1 overactivation, resulting from widespread DNA damage, accelerates

Structures and Mechanisms of Enzymes Employed in the Synthesis and Degradation of PARP-Dependent Protein ADP-Ribosylation

“…ARH3 has lower specific activity against PAR than PARG. The latest data show that ARH3 physiological function seems to be the hydrolysis of the protein-free PAR that gets released during PARP-dependent apoptotic response (Mashimo et al, 2013).…”

Poly(ADP-ribose) polymerases as modulators of mitochondrial activity

“…Several PARG isoforms exist, due to alternative splicing, that can be found in most cellular compartments [9]. Besides PARG, ADP-ribosylacceptor hydrolase 3 (ARH3), ADP-ribosyl lyase and macrodomain-containing proteins are also important regulators of cellular PAR levels [2,5,[9][10][11]. ADPR can be further metabolized to AMP by nucleoside diphosphate linked to X (NUDIX) pyrophosphatases [12].…”

Modulation of Poly(ADP-Ribose) Polymerase-1 (PARP-1)-Mediated Oxidative Cell Injury by Ring Finger Protein 146 (RNF146) in Cardiac Myocytes

“…The present report provides evidence for these phenomena both in an in vitro oxidatively stressed cardiomyocyte model and in an in vivo myocardial ischemiareperfusion model. We hypothesize that this mechanism (somewhat similarly to the caspase-mediated cleavage of PARP-1 mentioned earlier [36][37][38] and by the recently recognized degradation of PARP-1 by ADP-ribosyl-acceptor hydrolase 3 [50]) serves as a protective function during oxidant-mediated cell death, since it limits the degree of PARP-1 overactivation and the associated cellular energetic catastrophe and cell necrosis. Also, this mechanism may partially restore cellular energetic pools, perhaps in an attempt of the cell to switch the mode of cell death to a more regulated form (for example, apoptosis).…”