Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.4.2.30 (PARP)
13,611 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Poly(ADP-ribose) (PAR) has been identified as a DNA damage-inducible cell death signal upstream of apoptosis-inducing factor (AIF). PAR causes the translocation of AIF from mitochondria to the nucleus and triggers cell death. In living cells, PAR molecules are subject to dynamic changes pending on internal and external stress factors. Using RNA interference (RNAi), we determined the roles of poly(ADP-ribose) polymerases-1 and -2 (PARP-1, PARP-2) and poly(ADP-ribose) glycohydrolase (PARG), the key enzymes configuring PAR molecules, in cell death induced by an alkylating agent. We found that PARP-1, but not PARP-2 and PARG, contributed to alkylation-induced cell death. Likewise, AIF translocation was only affected by PARP-1. PARP-1 seems to play a major role configuring PAR as a death signal involving AIF translocation regardless of the death pathway involved.
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PMID:The roles of poly(ADP-ribose)-metabolizing enzymes in alkylation-induced cell death. 1820 25

Oxidative stress results from an oxidant/antioxidant imbalance, an excess of oxidants and/or a depletion of antioxidants. A vast amount of circumstantial evidence implicates oxygen-derived free radicals (especially, superoxide and hydroxyl radical) and high energy oxidants (such as peroxynitrite) as mediators of secondary damage associated with spinal cord injury. Reactive oxygen species (ROS) (e.g., superoxide, peroxynitrite, hydroxyl radical and hydrogen peroxide) are all potential reactants capable of initiating DNA single strand breakage, with subsequent activation of the nuclear enzyme poly (ADP ribose) synthetase (PARS), leading to eventual severe energy depletion of the cells, and necrotic-type cell death. Moreover, Poly(ADP-ribosyl)ation is regulated by the synthesizing enzyme poly(ADP-ribose) polymerase-1 (PARP-1) and the degrading enzyme poly(ADP-ribose) glycohydrolase (PARG). Here, we review the roles of ROS, PARP-1 and PARG in spinal cord injury as well as the beneficial effect of the in vivo treatment with novel pharmacological tools (e.g. peroxynitrite decomposition catalysts, selective superoxide dismutase mimetics (SODm), PARP-1 and PARG inhibitors.
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PMID:Role of free radicals and poly(ADP-ribose)polymerase-1 in the development of spinal cord injury: new potential therapeutic targets. 1828 3

A dissection of plant defense pathways was initiated through gene expression profiling of the responses of a single Arabidopsis thaliana genotype to isogenic Pseudomonas syringae strains expressing one of four different cloned avirulence (avr) genes. Differences in the expression profiles elicited by different resistance (R)-avr interactions were observed. A role for poly(ADP-ribosyl)ation in plant defense responses was suggested initially by the upregulated expression of genes encoding NUDT7 and poly(ADP-ribose) glycohydrolase in multiple R-avr interactions. Gene knockout plant lines were tested for 20 candidate genes identified by the expression profiling, and Arabidopsis NUDT7 mutants allowed less growth of virulent P. syringae (as previously reported) but also exhibited a reduced hypersensitive-response phenotype. Inhibitors of poly(ADP-ribose) polymerase (PARP) disrupted FLS2-mediated basal defense responses such as callose deposition. EIN2 (ethylene response) and IXR1 and IXR2 (cellulose synthase) mutants impacted the FLS2-mediated responses that occur during PARP inhibition, whereas no impacts were observed for NPR1, PAD4, or NDR1 mutants. In the expression profiling work, false-positive selection and grouping of genes was reduced by requiring simultaneous satisfaction of statistical significance criteria for each of three separate analysis methods, and by clustering genes based on statistical confidence values for each gene rather than on average fold-change of transcript abundance.
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PMID:Discovery of ADP-ribosylation and other plant defense pathway elements through expression profiling of four different Arabidopsis-Pseudomonas R-avr interactions. 1839 24

Poly(ADP-ribose) is found to be involved in many physiological or pathological processes. It is mainly modulated by poly(ADP-ribose) polymerase (PARP) and poly(ADP-ribose) glycohydrolase (PARG). Either PARP or PARG is associated with the neuronal death in a variety of neurodegenerative diseases. Cumulative data have suggested that poly(ADP-ribose) regulation might have a therapeutic value in neurotoxicity-induced neuron damage, probably due to the inhibition of apoptosis, suppressing of inflammation and activation of cell survival signaling. We hypothesize poly(ADP-ribose) play an important role in seizures-induced neuron death. Seizures can lead to neuron degeneration as for the exitotoxity of glutamate. Recently, it is indicated seizures also can trigger PARP activation. Further investigation is needed to determine whether poly(ADP-ribose) signal is a therapeutic target for seizures-induced injury.
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PMID:Poly(ADP-ribose) signal in seizures-induced neuron death. 1841 97

TRPM2 cation channels are widely expressed in the immune system and are thought to play a role in immune cell responses to oxidative stress. Patch clamp analyses suggest that TRPM2 channel activation can occur through a direct action of oxidants on TRPM2 channels or indirectly through the actions of a related group of adenine nucleotide 2nd messengers. However, the contribution of each gating mechanism to oxidative stress-induced TRPM2 activation in lymphocytes remains undefined. To better understand the molecular events leading to TRPM2 activation in lymphocytes, we analyzed oxidative stress-induced turnover of intracellular NAD, the metabolic precursor of adenine nucleotide 2nd messengers implicated in TRPM2 gating, and oxidative stress-induced TRPM2-mediated currents and Ca2+ transients in DT40 B cells. TRPM2-dependent Ca2+ entry did not influence the extent or time course of oxidative stress-induced turnover of NAD. Furthermore, expression of oxidative stress-activated poly(ADP-ribose) polymerases (PARPs) was required for oxidative stress-induced NAD turnover, TRPM2 currents, and TRPM2-dependent Ca2+ transients; no oxidant-induced activation of TRPM2 channels could be detected in PARP-deficient cells. Together, our results suggest that during conditions of oxidative stress in lymphocytes, TRPM2 acts as a downstream effector of the PARP/poly(ADP-ribose) glycohydrolase pathway through PARP-dependent formation of ADP-ribose.
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PMID:The Poly(ADP-ribose) polymerase PARP-1 is required for oxidative stress-induced TRPM2 activation in lymphocytes. 1859 83

Poly(ADP-ribose) polymerase (PARP) is known to be activated under conditions of oxidative stress and/or radiation exposure. The role of this enzyme has been well demonstrated in the streptozotocin (STZ) induced model of diabetes. Inhibition of PARP by specific inhibitors is known to prevent the development of STZ induced diabetic nephropathy by reduction in oxidative stress induced apoptosis. This study shows for the first time the role of poly(ADP-ribose) glycohydrolase (PARG) inhibitors as an alternative approach for inhibition of PARP. Gallotannin (20 mg/kg/day, i.p.) treatment for 4 weeks led to a significant reduction in the levels of plasma creatinine which is a well known marker for diabetic nephropathy. Treatment with gallotannin resulted in protection up to a certain level of glomerular damage, suggesting compensatory glomerular hypertrophy. As a PARG inhibitor gallotannin treatment also showed protection in PARP cleavage which is a hallmark for apoptotic cell death signifying the protective role of gallotannin in cell death signaling.
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PMID:Gallotannin ameliorates the development of streptozotocin-induced diabetic nephropathy by preventing the activation of PARP. 1869 96

Poly(ADP-ribosyl)ation is a posttranslational modification of proteins in higher eukaryotes mediated by poly(ADP-ribose) polymerases (PARPs) that is involved in many physiological processes such as DNA repair, transcription, cell division, and cell death. Biochemical studies together with PARP-1- or PARP-2-deficient cellular and animal models have revealed the redundant but also complementary functions of the two enzymes in the surveillance and maintenance of genome integrity. Poly(ADP-ribose) is degraded by the endo- and exo-glycosidase activities of poly(ADP-ribose) glycohydrolase (PARG). In this chapter, biochemical and immunofluorescence methods are described for detecting and assaying PARPs and PARG.
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PMID:Detection of the nuclear poly(ADP-ribose)-metabolizing enzymes and activities in response to DNA damage. 1895 Nov 90

Phosphorylation is a very common post-translational modification event known to modulate a wide range of biological responses. Beyond the regulation of protein activity, the interrelation of phosphorylation with other post-translational mechanisms is responsible for the control of diverse signaling pathways. Several observations suggest that phosphorylation of poly(ADP-ribose) polymerase-1 (PARP-1) regulates its activity. There is also accumulating evidence to suggest the establishment of phosphorylation-dependent assembly of PARP-1-associated multiprotein complexes. Although it is relatively straightforward to demonstrate phosphorylation of a defined target, identification of the actual amino acids involved still represents a technical challenge for many laboratories. With the use of a combination of bioinformatics-based predictions tools for generic and kinase-specific phosphorylation sites, in vitro phosphorylation assays and mass spectrometry analysis, we investigated the phosphorylation profile of PARP-1 and poly(ADP-ribose) glycohydrolase (PARG), two major enzymes responsible for poly(ADP-ribose) turnover. Mass spectrometry analysis revealed the phosphorylation of several serine/threonine residues within important regulatory domains and motifs of both enzymes. With the use of in vivo microirradiation-induced DNA damage, we show that altered phosphorylation at specific sites can modify the dynamics of assembly and disassembly of PARP-1 at sites of DNA damage. By documenting and annotating a collection of known and newly identified phosphorylation sites, this targeted proteomics study significantly advances our understanding of the roles of phosphorylation in the regulation of PARP-1 and PARG.
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PMID:Proteomic investigation of phosphorylation sites in poly(ADP-ribose) polymerase-1 and poly(ADP-ribose) glycohydrolase. 1910 32

Poly(ADP-ribose) polymerases (PARPs) convert NAD to polymers of ADP-ribose that are converted to free ADP-ribose by poly(ADP-ribose) glycohydrolase (PARG). The activation of the nuclear enzyme PARP-1 following genotoxic stress has been linked to release of apoptosis inducing factor from the mitochondria, but the mechanisms by which signals are transmitted between nuclear and mitochondrial compartments are not well understood. The study reported here has examined the relationship between PARG and mitochondria in HeLa cells. Endogenous PARG associated with the mitochondrial fraction migrated in the range of 60 kDa. Transient transfection of cells with PARG expression constructs with amino acids encoded by exon 4 at the N-terminus was targeted to the mitochondria as demonstrated by subcellular fractionation and immunofluorescence microscopy of whole cells. Deletion and missense mutants allowed identification of a canonical N-terminal mitochondrial targeting sequence consisting of the first 16 amino acids encoded by PARG exon 4. Sub-mitochondrial localization experiments indicate that this mitochondrial PARG isoform is targeted to the mitochondrial matrix. The identification of a PARG isoform as a component of the mitochondrial matrix raises several interesting possibilities concerning mechanisms of nuclear-mitochondrial cross talk involved in regulation of cell death pathways.
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PMID:A specific isoform of poly(ADP-ribose) glycohydrolase is targeted to the mitochondrial matrix by a N-terminal mitochondrial targeting sequence. 1938 96

Upon massive DNA damage, hyperactivation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP)-1 causes severe depletion of intracellular NAD and ATP pools as well as mitochondrial dysfunction. Thus far, the molecular mechanisms contributing to PARP-1-dependent impairment of mitochondrial functioning have not been identified. We found that degradation of the PARP-1 product poly(ADP-ribose) through the concerted actions of poly(ADP-ribose) glycohydrolase and NUDIX (nucleoside diphosphate-X) hydrolases leads to accumulation of AMP. The latter, in turn, inhibits the ADP/ATP translocator, prompting mitochondrial energy failure. For the first time, our findings identify NUDIX hydrolases as key enzymes involved in energy derangement during PARP-1 hyperactivity. Also, these data disclose unanticipated AMP-dependent impairment of mitochondrial exchange of adenine nucleotides, which can be of relevance to organelle functioning and disease pathogenesis.
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PMID:Poly(ADP-ribose) catabolism triggers AMP-dependent mitochondrial energy failure. 1941 Dec 52


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