Deficiency of terminal ADP-ribose protein glycohydrolase TARG1/C6orf130 in neurodegenerative disease

Sharifi, Reza; Morra, Rosa; Appel, C. Denise; Tallis, Michael; Chioza, Barry A.; Jankevicius, Gytis; Simpson, Michael A.; Matić, Ivan; Ozkan, Ege; Golia, Barbara; Schellenberg, M.J.; Weston, Ria; Williams, Jason; Rossi, Marianna Nicoletta; Galehdari, Hamid; Krahn, J.M.; Wan, Alexander; Trembath, Richard C.; Crosby, Andrew H.; Ahel, Dragana; Hay, Ronald T.; Ladurner, Andreas G.; Timinszky, Gyula; Williams, R. Scott; Ahel, Ivan

doi:10.1038/emboj.2013.51

Cited by 281 publications

(475 citation statements)

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“…In addition, a recent study identified another potential candidate, terminal ADP ribose glycohydrolase TARG (C6orf130), which generates protein-free PAR from poly-ADP ribosylated proteins. In addition to PAR, TARG removes the terminal ADP ribose linked to glutamate in poly-ADP ribosylated proteins (36). TARG by generating protein-free PAR may contribute to parthanatos.…”

Section: Discussionmentioning

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.

142

156

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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

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Section: Discussionmentioning

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.

142

156

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“…structure (44). At least one additional protein-i.e., the ADPribose protein glycohydrolase TARG1-has been recently shown to assist PARG in full removal of PAR chains from target proteins and has been implicated in human disease (45); it will thus be important to test the possible involvement of this and possibly other PAR-degrading enzymes in the maintenance of genome stability during replication.…”

Section: Discussionmentioning

confidence: 99%

Poly(ADP-Ribosyl) Glycohydrolase Prevents the Accumulation of Unusual Replication Structures during Unperturbed S Phase

Chaudhuri

Ahuja

Herrador

et al. 2015

Molecular and Cellular Biology

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Poly(ADP-ribosyl)ation (PAR) has been implicated in various aspects of the cellular response to DNA damage and genome stability. Although 17 human poly(ADP-ribose) polymerase (PARP) genes have been identified, a single poly(ADP-ribosyl) glycohydrolase (PARG) mediates PAR degradation. Here we investigated the role of PARG in the replication of human chromosomes. We show that PARG depletion affects cell proliferation and DNA synthesis, leading to replication-coupled H2AX phosphorylation. Furthermore, PARG depletion or inhibition per se slows down individual replication forks similarly to mild chemotherapeutic treatment. Electron microscopic analysis of replication intermediates reveals marked accumulation of reversed forks and single-stranded DNA (ssDNA) gaps in unperturbed PARG-defective cells. Intriguingly, while we found no physical evidence for chromosomal breakage, PARG-defective cells displayed both ataxia-telangiectasia-mutated (ATM) and ataxia-Rad3-related (ATR) activation, as well as chromatin recruitment of standard double-strand-break-repair factors, such as 53BP1 and RAD51. Overall, these data prove PAR degradation to be essential to promote resumption of replication at endogenous and exogenous lesions, preventing idle recruitment of repair factors to remodeled replication forks. Furthermore, they suggest that fork remodeling and restarting are surprisingly frequent in unperturbed cells and provide a molecular rationale to explore PARG inhibition in cancer chemotherapy.C ellular responses are crucial for the adaptability and survival of a cell exposed to different types of endogenous and exogenous stress. The DNA damage response (DDR) consists of one such defense mechanism in response to different types of insults to the DNA. Poly(ADP)ribosylation of proteins is one of the quickest cellular responses to DNA damage and is brought about by proteins of the poly(ADP) ribose polymerase family (PARP), mostly PARP1 (1). Upon being recruited to sites of the DNA damage, NAD ϩ is used as a substrate by PARP to synthesize negatively charged poly(ADP-ribosyl)ation (PAR) polymers onto itself and also its target proteins (1). Through this posttranslational modification, PARP targets a variety of nuclear proteins to facilitate the recruitment of DNA repair factors to sites of damage (2, 3). Accordingly, PARP-1 or PARP-2-deficient mice and mouse embryonic fibroblasts show chromosomal aberrations and various DNA repair defects (4-6).Inhibition of PARP has become a promising therapeutic approach for the treatment of certain types of cancer (7). It was shown that PARP inhibitors could selectively kill homologous recombination (HR)-deficient cancer cells (8, 9). The reason behind the sensitivity of HR-deficient cells to PARP inhibition is thought to be the accumulation of single-stranded DNA (ssDNA) breaks in the absence of PAR synthesis, leading to replication fork collapse and double-stranded breaks (DSBs), which would then require HR factors for repair (8,10). Recently, PARP activity has also been reported to play a ro...

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“…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). The NUDIX family of hydrolases can hydrolyze PAR chains by targeting the phosphodiester bond in the protein-proximal ADP-ribose unit, which results in the formation of a phosphoribose moiety attached to the acceptor amino acid (Daniels et al 2015b).…”

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%

“…a See Kalisch et al (2012), Feijs et al (2013), Krietsch et al (2013), Hottiger (2015), Teloni and Altmeyer (2016), and Rack et al (2016) as well as references therein for a more comprehensive listing of ARBDs. 2006), PAR glycohydrolase (PARG) (Slade et al 2011), TARG/C6orf130 (Sharifi et al 2013), MacroD1 and MacroD2 Rosenthal et al 2013), and the NUDIX family of hydrolases (Daniels et al 2015b). Many of these enzymes contain a macrodomain fold, which allows them to interact with ADP-ribosylated substrates.…”

Section: Adp-ribose and Par Hydrolases: Erasersmentioning

confidence: 99%

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

2017

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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.

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Deficiency of terminal ADP-ribose protein glycohydrolase TARG1/C6orf130 in neurodegenerative disease

Cited by 281 publications

References 44 publications

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

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

Poly(ADP-Ribosyl) Glycohydrolase Prevents the Accumulation of Unusual Replication Structures during Unperturbed S Phase

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

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