ADP-ribosylhydrolase 3 (ARH3), Not Poly(ADP-ribose) Glycohydrolase (PARG) Isoforms, Is Responsible for Degradation of Mitochondrial Matrix-associated Poly(ADP-ribose)

Niere, Marc; Mashimo, Masato; Agledal, Line; Dölle, Christian; Kasamatsu, Atsushi; Katō, Jirō; Moss, Joel; Ziegler, Mathias

doi:10.1074/jbc.m112.349183

Cited by 97 publications

(108 citation statements)

References 43 publications

Supporting

Mentioning

105

Contrasting

Order By: Relevance

“…Certain PARPs, such as PARP-2, PARP-3, and PARP-7, exhibit differential localization in the nucleus and the cytoplasm during different phases of the cell cycle (Vyas et al 2013). Moreover, as mentioned in the previous section, the ADP-ribose hydrolases also exhibit distinct subcellular localizations (Niere et al 2012;Jankevicius et al 2013;Sharifi et al 2013). Taken together, these observations suggest that the compartmentalization of the "feeders," "writers," and "erasers" could be essential for rapid and coordinated changes in ADP-ribosylation in different subcellular milieus.…”

Section: Nicotinamide Mononucleotide Adenylyl Transferases (Nmnats): mentioning

confidence: 82%

“…Many of these enzymes contain a macrodomain fold, which allows them to interact with ADP-ribosylated substrates. Both PARG and ARH3 catalyze PAR chain degradation through endoglycocidic and exoglycocidic activities, which results in the cleavage of the ribose-ribose bonds but leaves a terminal ADP-ribose moiety attached to the acceptor amino acid residue of the substrate (Oka et al 2006;Slade et al 2011;Niere et al 2012). In contrast, TARG, MacroD1, and MacroD2 can hydrolyze the ester bond between the ribose and acceptor amino acids (aspartates or glutamates), thus facilitating the complete removal of the ADP-ribose moiety Rosenthal et al 2013;Sharifi et al 2013).…”

Section: Adp-ribose and Par Hydrolases: Erasersmentioning

confidence: 99%

“…For example, the accumulation of PAR due to loss of PARG activity causes early embryonic lethality as well as increased sensitivity to genotoxic stress (Koh et al 2004). Interestingly, the "erasers" have different subcellular localizations: MacroD1 and ARH3 localize to the mitochondria (Niere et al 2012;Jankevicius et al 2013), whereas MacroD2 and TARG localize predominantly to the nucleus Sharifi et al 2013). This suggests possible localized turnover of PAR, adding another layer of complexity to the regulation of cellular processes by ADP-ribosylation.…”

Section: Adp-ribose and Par Hydrolases: Erasersmentioning

confidence: 99%

See 2 more Smart Citations

PARPs and ADP-ribosylation: recent advances linking molecular functions to biological outcomes

2017

View full text Add to dashboard Cite

The discovery of poly(ADP-ribose) >50 years ago opened a new field, leading the way for the discovery of the poly(ADP-ribose) polymerase (PARP) family of enzymes and the ADP-ribosylation reactions that they catalyze. Although the field was initially focused primarily on the biochemistry and molecular biology of PARP-1 in DNA damage detection and repair, the mechanistic and functional understanding of the role of PARPs in different biological processes has grown considerably of late. This has been accompanied by a shift of focus from enzymology to a search for substrates as well as the first attempts to determine the functional consequences of site-specific ADP-ribosylation on those substrates. Supporting these advances is a host of methodological approaches from chemical biology, proteomics, genomics, cell biology, and genetics that have propelled new discoveries in the field. New findings on the diverse roles of PARPs in chromatin regulation, transcription, RNA biology, and DNA repair have been complemented by recent advances that link ADP-ribosylation to stress responses, metabolism, viral infections, and cancer. These studies have begun to reveal the promising ways in which PARPs may be targeted therapeutically for the treatment of disease. In this review, we discuss these topics and relate them to the future directions of the field.ADP-ribosylation is a reversible post-translational modification (PTM) of proteins resulting in the covalent attachment of a single ADP-ribose unit [i.e., mono(ADP-ribose) (MAR)] or polymers of ADP-ribose units [i.e., poly(ADP-ribose) (PAR)] on a variety of amino acid residues on target proteins (Gibson and Kraus 2012;Daniels et al. 2015a). This modification is mediated by a diverse group of ADPribosyl transferase (ADPRT) enzymes that use ADP-ribose units derived from β-NAD + to catalyze the ADP-ribosylation reaction. These enzymes include bacterial ADPRTs (e.g., cholera toxin and diphtheria toxin) as well as members of three different protein families in yeast and animals: (1) arginine-specific ecto-enzymes (ARTCs), (2) sirtuins, and (3) PAR polymerases (PARPs) . Surprisingly, a recent study showed that the bacterial toxin DarTG can ADP-ribosylate DNA . How this fits into the broader picture of cellular ADP-ribosylation has yet to be determined.In this review, we focus on the mono(ADP-ribosyl)ation (MARylation) and poly(ADP-ribosyl)ation (PARylation) of glutamate, aspartate, and lysine residues by PARP family members. While many reviews have been written on PARPs in the past decade, we highlight the current trends and ideas in the field, in particular those discoveries that have been published in the past 2-3 years.

show abstract

Section: Nicotinamide Mononucleotide Adenylyl Transferases (Nmnats): mentioning

confidence: 82%

Section: Adp-ribose and Par Hydrolases: Erasersmentioning

confidence: 99%

Section: Adp-ribose and Par Hydrolases: Erasersmentioning

confidence: 99%

See 1 more Smart Citation

PARPs and ADP-ribosylation: recent advances linking molecular functions to biological outcomes

2017

View full text Add to dashboard Cite

show abstract

“…There is consensus in the literature that mitochondria possess glycohydrolase activity (the activity necessary for PAR degradation) with ARH3 being the major component [28]. Although the existence of mitochondrial PARP activity is debated, there are data that show the presence of PARylated proteins in isolated rat liver mitochondria [29,30], mitochondrial PARP activity [29,31], or identify mitochondrial malate dehydrogenase as a PARP-1 interacting protein [32].…”

Section: Glossarymentioning

confidence: 99%

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

Bai

Nagy

Fodor

et al. 2015

Trends in Endocrinology & Metabolism

100

View full text Add to dashboard Cite

Activation of poly(ADP-ribose) polymerases-1 and -2 (PARP-1 and PARP-2) deteriorates mitochondrial activity. NAD + and ATP degradation are not coupled to each other upon PARP activation. PARPs interact with transcription factors modulating mitochondrial activity. PARPs can be positive regulators of mitochondrial output under sublethal stress. PARP inhibition is an attractive target for treating mitochondrial dysfunction.

show abstract

“…Unlike the multigene PARP family, the single parg gene, via alternative splicing, gives rise to isoforms with different subcellular localizations and activities (18). Full-length, 110-kDa PARG is found in the nucleus, with other forms in the cytoplasm and mitochondria (19)(20)(21). In contrast to that of PARP1, the action of PARG in response to DNA damage is still controversial.…”

mentioning

confidence: 99%

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

Mashimo

Katō

Moss

2013

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

142

156

View full text Add to dashboard Cite

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

show abstract

ADP-ribosylhydrolase 3 (ARH3), Not Poly(ADP-ribose) Glycohydrolase (PARG) Isoforms, Is Responsible for Degradation of Mitochondrial Matrix-associated Poly(ADP-ribose)

Cited by 97 publications

References 43 publications

PARPs and ADP-ribosylation: recent advances linking molecular functions to biological outcomes

PARPs and ADP-ribosylation: recent advances linking molecular functions to biological outcomes

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

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

Contact Info

Product

Resources

About