Identification and Characterization of a Mammalian 39‐kDa Poly(ADP‐ribose) Glycohydrolase

Oka, Shunya; Katō, Jirō; Moss, Joel

doi:10.1096/fasebj.20.4.a45-c

Cited by 16 publications

(24 citation statements)

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“…It is worth pointing out that ARH3 is considerably less active toward PAR chains than PARG in vitro. 205 On that account, it may not be surprising that Arh3 knockout mice, unlike Parg −/− animals, are healthy. In Arh3 −/− mouse embryo fibroblast (MEF) cells an increase in PAR chains after DNA damage is observed, indicating that ARH3 is involved in controlling PAR stability.…”

Section: Hydrolases 41 Poly-adp-ribose Chain Degrading Enzymessupporting

confidence: 77%

“…204 In addition to PARG, ADP-ribosyl-acceptor hydrolase (ARH) 3 has also been described as a PAR-degrading enzyme. 205,206 Moreover, ARH3 hydrolyzes O-acetyl-ADPr, the product of the deacetylation reaction catalyzed by sirtuins. 207 Thus, so far these are the two only enzymes that can degrade PAR chains (Figure 3).…”

Section: Hydrolases 41 Poly-adp-ribose Chain Degrading Enzymesmentioning

confidence: 99%

“…219 Unlike ARH1, ARH3 is unable to hydrolyze the Arg−ADPr bond as well as several other amino acid−ADPr bonds, which led to the suggestion that ARH3, similar to PARG, cannot fully revert ADP-ribosylation. 205,235 However, this interpretation is in need of revision because most recent findings describe ARH3 as the hydrolase that cleaves the Ser−ADPr bond (personal communication of Dr. M. Hottiger, University of Zurich). 236 Although many of the details have not been clarified yet, this important finding suggests that ARH3 is capable of fully reverting the activity of ARTD1 in complex with histone PARylation factor 1 (HPF1) as described in more detail below.…”

Section: Hydrolases 41 Poly-adp-ribose Chain Degrading Enzymesmentioning

confidence: 99%

“…237 ARH3 is ubiquitously expressed in human and mouse tissues and localized in the nucleus, in the cytosol, and in mitochondria. 205,216,230 ARH3, which has an MTS, is as far as analyzed the only PAR-degrading enzyme in mitochondria. 215,216 However, an enzyme with PAR-forming activity has not yet been found in mitochondria, and therefore the functional relevance of ARH3 in mitochondria is not clear.…”

Section: Hydrolases 41 Poly-adp-ribose Chain Degrading Enzymesmentioning

confidence: 99%

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ADP-Ribosylation, a Multifaceted Posttranslational Modification Involved in the Control of Cell Physiology in Health and Disease

et al. 2017

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Posttranslational modifications (PTMs) regulate protein functions and interactions. ADP-ribosylation is a PTM, in which ADP-ribosyltransferases use nicotinamide adenine dinucleotide (NAD) to modify target proteins with ADP-ribose. This modification can occur as mono- or poly-ADP-ribosylation. The latter involves the synthesis of long ADP-ribose chains that have specific properties due to the nature of the polymer. ADP-Ribosylation is reversed by hydrolases that cleave the glycosidic bonds either between ADP-ribose units or between the protein proximal ADP-ribose and a given amino acid side chain. Here we discuss the properties of the different enzymes associated with ADP-ribosylation and the consequences of this PTM on substrates. Furthermore, the different domains that interpret either mono- or poly-ADP-ribosylation and the implications for cellular processes are described.

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Section: Hydrolases 41 Poly-adp-ribose Chain Degrading Enzymessupporting

confidence: 77%

Section: Hydrolases 41 Poly-adp-ribose Chain Degrading Enzymesmentioning

confidence: 99%

Section: Hydrolases 41 Poly-adp-ribose Chain Degrading Enzymesmentioning

confidence: 99%

Section: Hydrolases 41 Poly-adp-ribose Chain Degrading Enzymesmentioning

confidence: 99%

See 2 more Smart Citations

ADP-Ribosylation, a Multifaceted Posttranslational Modification Involved in the Control of Cell Physiology in Health and Disease

et al. 2017

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“…In addition to the “writers” and “readers,” “eraser” enzymes, including PAR glycohydrolase (PARG) and ADP-ribosylhydrolase 3 (ARH3), recognize specific ADPR modifications through the ARBDs and catalyze PAR chain degradation through endo- and exoglycocidic activities. Their activities leave the terminal ADPR moiety attached to the acceptor amino acid residue of the substrate (Barkauskaite et al, 2013; Niere et al, 2012; Oka et al, 2006; Slade et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Development and Characterization of PAR-Trackers: New Tools for Detecting Poly(ADP-ribose) In Vitro and In Vivo

Kraus

Challa

Ryu

et al. 2021

Preprint

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ADP-ribosylation (ADPRylation) is a reversible post-translation modification resulting in the covalent attachment of ADP-ribose (ADPR) moieties on substrate proteins. Naturally-occurring protein motifs and domains, including WWEs, PBZs, and macrodomains, act as 'readers' for protein-linked ADPR. Although recombinant, antibody-like ADPR detection reagents containing these readers have facilitated the detection of ADPR, they are limited in their ability to capture the dynamic nature of ADPRylation. Herein, we describe and characterize a set of poly(ADP-ribose) (PAR) Trackers (PAR-Ts) - optimized dimerization-dependent or split-protein reassembly PAR sensors in which a naturally occurring PAR binding domain, WWE, was fused to both halves of dimerization-dependent GFP (ddGFP) or split Nano Luciferase (NanoLuc), respectively. We demonstrate that these new tools allow the detection and quantification of PAR levels in extracts, living cells, and living tissues with greater sensitivity, as well as temporal and spatial precision. Importantly, these sensors detect changes in cellular ADPR levels in response to physiological cues (e.g., hormone-dependent induction of adipogenesis without DNA damage), as well as xenograft tumor tissues in living mice. Our results indicate that PAR Trackers have broad utility for detecting ADPR in many different experimental and biological systems.

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Genomic and biological aspects of resistance to selective poly(ADP‐ribose) glycohydrolase inhibitor PDD00017273 in human colorectal cancer cells

et al. 2022

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Background: Poly(ADP-ribose) glycohydrolase (PARG) is a key enzyme in poly(ADPribose) (PAR) metabolism and a potential anticancer target. Many drug candidates have been developed to inhibit its enzymatic activity. Additionally, PDD00017273 is an effective and selective inhibitor of PARG at the first cellular level.Aims: Using human colorectal cancer (CRC) HCT116 cells, we investigated the molecular mechanisms and tumor biological aspects of the resistance to PDD00017273.Methods and results: HCT116R PDD , a variant of the human CRC cell line HCT116, exhibits resistance to the PARG inhibitor PDD00017273. HCT116R PDD cells contained specific mutations of PARG and PARP1, namely, PARG mutation Glu352Gln and PARP1 mutation Lys134Asn, as revealed by exome sequencing. Notably, the levels of PARG protein were comparable between HCT116R PDD and HCT116. In contrast, the PARP1 protein levels in HCT116R PDD were significantly lower than those in HCT116. Consequently, the levels of intracellular poly(ADP-ribosyl)ation were elevated in HCT116R PDD compared to HCT116. Interestingly, HCT116R PDD cells did not exhibit cross-resistance to COH34, an additional PARG inhibitor. Conclusion:Our findings suggest that the mutated PARG acquires PDD00017273 resistance due to structural modifications. In addition, our findings indicate that PDD00017273 resistance induces mutation and PARP downregulation. These discoveries collectively provide a better understanding of the anticancer candidate PARG inhibitors in terms of resistance mechanisms and anticancer strategies.

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Identification and Characterization of a Mammalian 39‐kDa Poly(ADP‐ribose) Glycohydrolase

Cited by 16 publications

References 0 publications

ADP-Ribosylation, a Multifaceted Posttranslational Modification Involved in the Control of Cell Physiology in Health and Disease

ADP-Ribosylation, a Multifaceted Posttranslational Modification Involved in the Control of Cell Physiology in Health and Disease

Development and Characterization of PAR-Trackers: New Tools for Detecting Poly(ADP-ribose) In Vitro and In Vivo

Genomic and biological aspects of resistance to selective poly(ADP‐ribose) glycohydrolase inhibitor PDD00017273 in human colorectal cancer cells

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