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Query: EC:3.2.1.143 (poly(ADP-ribose) glycohydrolase)
 208 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nicotinamide can facilitate DNA repair by inhibiting poly(ADP-ribose) polymerase, increasing NAD levels and adjusting other related enzyme activities. This review will summarize recent work on the design of poly(ADP-ribose) polymerase inhibitors, poly(ADP-ribose) glycohydrolase inhibitors and will discuss the possible use of drugs that interact with NAD synthetic enzymes.
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PMID:Medicinal chemistry of nicotinamide in the treatment of ischemia and reperfusion. 1237 74

In the present study, we examined the role and the mechanism of poly(ADP-ribose) polymerase (PARP) and poly(ADP-ribose) glycohydrolase (PARG) activation in zinc-induced cell death in cortical culture. After brief exposure to 400 microM zinc, cortical cells exhibited DNA fragmentation, increased poly(ADP-ribosyl)ation, and decreased levels of nicotinamide adenine dinucleotide (NAD) and ATP and subsequently underwent cell death. Inhibitors of PARP/PARG attenuated both zinc-induced NAD/ATP depletion and cell death, thereby implicating the PARP/PARG cascade in these processes. The zinc-inducible enzymes NADPH oxidase and neuronal nitric oxide synthase (nNOS) contributed to PARP activation as their inhibitors attenuated zinc-induced poly(ADP-ribosyl)ation. Levels of nitric oxide and nitrites increased following zinc exposure, consistent with NOS activation. In addition, Western blots and RT-PCR analysis revealed that protein and mRNA levels of nNOS specifically increased following zinc exposure in a manner similar to that of NADPH oxidase. The present study demonstrates that induction of NADPH oxidase and nNOS actively contributes to PARP/PARG-mediated NAD/ATP depletion and cell death induced by zinc in cortical culture.
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PMID:The role of NADPH oxidase and neuronal nitric oxide synthase in zinc-induced poly(ADP-ribose) polymerase activation and cell death in cortical culture. 1242 87

The nuclear metabolism of poly(ADP-ribose) is mainly regulated by poly(ADP-ribose) polymerase-1 (PARP-1) and by poly(ADP-ribose) glycohydrolase (PARG). A PARP-like enzyme, V-PARP, and a PARG isoform are present in the extra-nuclear compartment of mammalian cells, even if poly(ADP-ribose) has never been detected therein. In this work, we demonstrate the ability of post-nuclear extracts from HeLa and HL60 cells to degrade synthetic 32P-polymers of ADP-ribose to ADP-ribose and, further, to AMP. This reaction implies the combined action of PARG and of an ADP-ribose-degrading activity, possibly corresponding to a phosphodiesterase and/or to an ADP-ribose pyrophosphatase. The inhibition of PARG or ADP-ribose-degrading enzymes allowed the demonstration that in vitro synthesized 32P-poly(ADP-ribose) is first digested to ADP-ribose monomers by a typical PARG reaction, and that ADP-ribose is further rapidly converted into AMP by an Mg(2+)-dependent activity. Collectively, our results demonstrate the ability of the human cell post-nuclear fraction to convert synthetic poly(ADP-ribose) into utilizable AMP units by the concerted action of PARG and ADP-ribose-degrading activities.
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PMID:Poly(ADP-ribose) degradation by post-nuclear extracts from human cells. 1262

Poly(ADP-ribose) is synthesized from nicotinamide adenine dinucleotide (NAD(+)) by poly(ADP-ribose) polymerase (PARP) and degraded by poly(ADP-ribose) glycohydrolase (PARG). Overactivation of the poly(ADP-ribose) pathway increases nicotinamide and decreases cellular NAD(+)/ATP, which leads to cell death. Blocking poly(ADP-ribose) metabolism by inactivating PARP has been shown to reduce ischemia injury. We investigated whether disrupting the poly(ADP-ribose) cycle by PARG inhibition could achieve similar protection. We demonstrate that either pre- or post-ischemia treatment with 40 mg/kg of N-bis-(3-phenyl-propyl)9-oxo-fluorene-2,7-diamide, a novel PARG inhibitor, significantly reduces brain infarct volumes by 40-53% in a rat model of focal cerebral ischemia. Our result provides the first evidence that PARG inhibitors can ameliorate ischemic brain damage in vivo, in support of PARG as a new therapeutic target for treating ischemia injury.
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PMID:Post-treatment with a novel PARG inhibitor reduces infarct in cerebral ischemia in the rat. 1283 3

Poly(ADP-ribose) and poly(ADP-ribose) polymerase (PARP) were discovered about 40 years ago, but their significance was not well elucidated until recently. In the early stage of the history of PARP, the presence of antibodies in the sera of human patients with lupus erythematosus indicated its natural occurrence. PARP, as well as the degrading enzyme, poly(ADP-ribose) glycohydrolase (PARG), are present in most eukaryotes except for yeasts. Studies that used inhibitors of PARP indicated the involvement of PARP and poly(ADP-ribose) in DNA damage repair, and eventually PARP was purified and the gene was cloned. Molecular analysis then revealed various functional domains, such as the one for binding to strand breaks of DNA. Parp-1-deficient and Parg-deficient cells showed, in general, enhanced sensitivity to the lethal effects of ionizing radiation and alkylating agents. Parp-1 knockout mouse embryonic stem cells developed into teratocarcinoma-like tumors when injected subcutaneously into nude mice, these tumors featuring giant cells similar to syncytiotrophoblastic giant cells with hyperploidy. Parp-1 was also found in centrosomes, suggesting that poly(ADP-ribose) and PARP-1 are functionally involved in the maintenance of chromatin structure and the equal distribution of chromosomes into daughter cells. Intriguing findings on the real biological significance continue to be generated, with new light shed on mechanisms of carcinogenesis and pointing to novel cancer treatments. Highlights during the last four decades of studies by laboratories focusing on poly(ADP-ribose)/PARP, including our own, are condensed and summarized in this review.
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PMID:Poly(ADP-ribose) and carcinogenesis. 1456 54

ATP-binding cassette (ABC) transporters are involved in the transport of multiple substrates across cellular membranes, including metabolites, proteins, and drugs. Employing a functional fluorochrome export assay, we found that UVB irradiation strongly inhibits the activity of ABC transporters. Specific inhibitors of poly(ADP-ribose) polymerase-1 (PARP-1) restored the function of ABC transporters in UVB-irradiated cells, and PARP-1-deficient cells did not undergo UVB-induced membrane transport inhibition. These data suggest that PARP-1 activation is necessary for ABC transporter functional downregulation. The hydrolysis of poly(ADP-ribose) by poly(ADP-ribose) glycohydrolase (PARG) was also required, since specific PARG inhibitors, which limit the production of ADP-ribose molecules, restored the function of ABC transporters. Furthermore, ADP-ribose molecules potently inhibited the activity of the ABC transporter P-glycoprotein. Hence, poly(ADP-ribose) metabolism appears to play a novel role in the regulation of ABC transporters.
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PMID:UV irradiation inhibits ABC transporters via generation of ADP-ribose by concerted action of poly(ADP-ribose) polymerase-1 and glycohydrolase. 1468 57

Poly(ADP-ribosyl)ation is an important post-translational modification which mostly affects nuclear proteins. The major roles of poly(ADP-ribose) synthesis are assigned to DNA damage signalling during base excision repair, apoptosis and excitotoxicity. The transient nature and modulation of poly(ADP-ribose) levels depend mainly on the activity of poly(ADP-ribose) polymerase-1 (PARP-1) and poly(ADP-ribose) glycohydrolase (PARG), the key catabolic enzyme of poly(ADP-ribose). Given the fact that PARG substrate, poly(ADP-ribose), is found almost exclusively in the nucleus and that PARG is mainly localized in the cytoplasm, we wanted to have a closer look at PARG subcellular localization in order to better understand the mechanism by which PARG regulates intracellular poly(ADP-ribose) levels. We examined the subcellular distribution of PARG and of its two enzymatically active C-terminal apoptotic fragments both biochemically and by fluorescence microscopy. Green fluorescent protein (GFP) fusion proteins were constructed for PARG (GFP-PARG), its 74 kDa (GFP-74) and 85 kDa (GFP-85) apoptotic fragments and transiently expressed in COS-7 cells. Localization experiments reveal that all three fusion proteins localize predominantly to the cytoplasm and that a fraction also co-localizes with the Golgi marker FTCD. Moreover, leptomycin B, a drug that specifically inhibits nuclear export signal (NES)-dependent nuclear export, induces a redistribution of GFP-PARG from the cytoplasm to the nucleus and this nuclear accumulation is even more pronounced for the GFP-74 and GFP-85 apoptotic fragments. This observation confirms our hypothesis for the presence of important regions in the PARG sequence that would allow the protein to engage in CRM1-dependent nuclear export. Moreover, the altered nuclear import kinetics found for the apoptotic fragments highlights the importance of PARG N-terminal sequence in modulating PARG nucleocytoplasmic trafficking properties.
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PMID:Alteration of poly(ADP-ribose) glycohydrolase nucleocytoplasmic shuttling characteristics upon cleavage by apoptotic proteases. 1472 Apr 66

Oxidative stress-induced cytotoxicity is mediated in part by accelerated poly-ADP ribosylation. Peroxynitrite and hydrogen peroxide cause DNA breakage triggering the activation of the DNA nick sensor enzyme poly(ADP-ribose) polymerase-1 (PARP-1). Overactivation of PARP-1 leads to cell dysfunction and cell death mainly due to depletion of NAD(+) (the substrate of PARP-1) and ATP. PARP-1 attaches most ADP-ribose residues onto itself, leading to downregulation of enzyme activity. Here, we have investigated the role of poly(ADP-ribose) glycohydrolase (PARG), the poly(ADP-ribose)-catabolyzing enzyme in oxidative stress-induced cytotoxicity in HaCaT cells. We have found that inhibition of PARG by gallotannin (GT) (50 microM) provided significant cytoprotection to peroxynitrite- or hydrogen peroxide-treated HaCaT cells, as assessed by lactate dehydrogenase release and propidium iodide uptake (parameters of necrotic cell death) as well as caspase activation (apoptotic parameter). GT pretreatment has also inhibited the depletion of cellular NAD(+) pools in hydrogen peroxide- or peroxynitrite-treated HaCaT cells. GT caused the accumulation of poly(ADP-ribose) and concomitant inhibition in cellular PARP activity in oxidatively stressed cells. Therefore, PARG is likely to contribute to maintaining the active state of PARP-1 by continuously removing inhibitory ADP-ribose residues from PARP-1.
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PMID:Cytoprotective effect of gallotannin in oxidatively stressed HaCaT keratinocytes: the role of poly(ADP-ribose) metabolism. 1498 57

Phenolic phytochemicals such as tannins, which are natural constituents of green tea, red wine, and other plant products, are considered to have cancer-preventive properties. An important endogenous mediator of tumorigenesis is the nuclear enzyme poly(ADP-ribose) polymerase 1 (PARP-1). PARP-1 synthesizes polymers of ADP-ribose (PAR), which, in turn, are degraded by the catabolic enzyme poly(ADP-ribose) glycohydrolase (PARG). In the present study, we investigated the effects of tannins on the level of PAR in HeLa nuclear extracts. The addition of tannins to nuclear extracts led to a 40-fold elevation of PAR-levels. The observed increased PAR-levels resulted from inhibition of the catalytic activity of PARG. Additionally, the human PARG cDNA was cloned and the recombinant enzyme was overexpressed and isolated. Recombinant PARG was immobilized using an affinity column composed of tannins covalently linked to Sepharose beads. Finally, an interaction between immobilized PARG and endogenous PARP-1 from HeLa cell extracts is demonstrated.
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PMID:Tannins elevate the level of poly(ADP-ribose) in HeLa cell extracts. 1508

Poly(ADP-ribosylation) is rapidly stimulated in cells following DNA damage. This posttranslational modification is regulated by the synthesizing enzyme poly(ADP-ribose) polymerase 1 (PARP-1) and the degrading enzyme poly(ADP-ribose) glycohydrolase (PARG). Although the role of PARP-1 in response to DNA damage has been studied extensively, the function of PARG and the impact of poly(ADP-ribose) homeostasis in various cellular processes are largely unknown. Here we show that by gene targeting in embryonic stem cells and mice, we specifically deleted the 110-kDa PARG protein (PARG(110)) normally found in the nucleus and that depletion of PARG(110) severely compromised the automodification of PARP-1 in vivo. PARG(110)-deficient mice were viable and fertile, but these mice were hypersensitive to alkylating agents and ionizing radiation. In addition, these mice were susceptible to streptozotocin-induced diabetes and endotoxic shock. These data indicate that PARG(110) plays an important role in DNA damage responses and in pathological processes.
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PMID:Depletion of the 110-kilodalton isoform of poly(ADP-ribose) glycohydrolase increases sensitivity to genotoxic and endotoxic stress in mice. 1528 15


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