Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.2.1.143 (poly(ADP-ribose) glycohydrolase)
 208 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Poly(ADP-ribosyl)ation plays an important role in modulating the cellular response to stress. The extent of poly(ADP-ribosyl)ation, chiefly via the activation of the poly(ADP-ribose) polymerase-1 (PARP-1), correlates with the severity of genotoxic stress and this determines the cellular response. Under mild and moderate stress, it plays important roles in DNA processing and it participates in the proinflammatory/cellular defense via transcriptional regulation. However, severe stress following acute neuronal injury causes the overactivation of PARP-1, which results in unregulated poly(ADP-ribose) (PAR) synthesis and widespread neuronal cell death. Previously, this PARP-1-dependent cell death mechanism was manifest solely through necrosis, but apoptotic mechanisms are also evident. Poly(ADP-ribosyl)ation directly induces the nuclear translocation of apoptosis-inducing factor, which results in caspase-independent cell death significant in many neurodegenerative conditions. Further, the hydrolysis of PAR by poly(ADP-ribose) glycohydrolase (PARG) has a protective role, since the accumulation of PAR leads to cell death by apoptosis. Thus, PAR signaling, regulated by PARP-1 and PARG, mediates cell death. Accordingly, modulation of PAR synthesis or degradation through the targeting of PARP-1 or PARG holds particular promise in the treatment of conditions such as cancer, stroke, and Parkinson's disease.
 ...
PMID:Mediation of cell death by poly(ADP-ribose) polymerase-1. 1591 29

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). Homeostasis of poly(ADP-ribosyl)ation has been proposed to be an important regulator for pathogenesis in multi-cellular organisms. Although the role of PARP-1 in tissue damage, inflammation and ischemia has been extensively studied, the function of PARG in various cellular processes is largely unknown. Recent studies using chemical inhibitors of PARG and genetically engineered Drosophila and mouse models that carry a disrupted PARG gene have started to shed new light on the biological function of PARG in vivo. These animal models and cells isolated from them will be useful for further validation of PARG as a potential pharmaceutical target to intervene the pathogenesis induced by acute tissue injury, ischemia and inflammation.
 ...
PMID:Role of poly(ADP-ribose) glycohydrolase (PARG) in shock, ischemia and reperfusion. 1591 38

Poly(ADP-ribose) polymerases (PARPs) catalyze the synthesis of ADP-ribose polymers and attach them to specific target proteins. To date, 6 members of this protein family in humans have been characterized. The best-known PARP, PARP-1, is located within the nucleus and has a major function in DNA repair but also in the execution of cell death pathways. Other PARP enzymes appear to carry out highly specific functions. Most prominently, the tankyrases modify telomere-binding proteins and thereby regulate telomere maintenance. Since only a single enzyme, poly(ADP-ribose) glycohydrolase (PARG), has been identified, which degrades poly(ADP-ribose), it is expected that this protein has important roles in PARP-mediated regulatory processes. This review summarizes recent observations indicating that poly(ADP-ribosylation) represents a major mechanism to regulate genomic stability both when DNA is damaged by exogenous agents and during cell division.
 ...
PMID:Poly(ADP-ribosylation) and genomic stability. 1595 54

PARG [poly(ADP-ribose) glycohydrolase] is the only known enzyme that catalyses the hydrolysis of poly(ADP-ribose), a branched polymer that is synthesized by the poly(ADP-ribose) polymerase family of enzymes. Poly(ADP-ribosyl)ation is a transient post-translational modification that alters the functions of the acceptor proteins. It has mostly been studied in the context of DNA-damage signalling or DNA transaction events, such as replication and transcription reactions. Growing evidence now suggests that poly(ADP-ribosyl)ation could have a much broader impact on cellular functions. To elucidate the roles that could be played by PARG, we performed a proteomic identification of PARG-interacting proteins by mass spectrometric analysis of PARG pulled-down proteins. In the present paper, we report that PARG is resident in FMRP (Fragile-X mental retardation protein)-associated messenger ribonucleoparticles complexes. The localization of PARG in these complexes, which are components of the translation machinery, was confirmed by sedimentation and microscopy analysis. A functional link between poly(ADP-ribosyl)ation modulation and FMRP-associated ribonucleoparticle complexes are discussed in a context of translational regulation.
 ...
PMID:Poly(ADP-ribose) glycohydrolase is a component of the FMRP-associated messenger ribonucleoparticles. 1611 24

Poly(ADP-ribose) (PAR) is a polymer synthesized by poly(ADP-ribose) polymerases (PARPs) and metabolized into free adenosine diphosphate (ADP)-ribose units by poly(ADP-ribose) glycohydrolase (PARG). Perturbations in PAR synthesis have been shown to play a key role in brain disorders including postischemic brain damage. A single parg gene but two PARG isoforms (110 and 60 kDa) have been detected in mouse cells. Complete suppression of parg gene causes early embryonic lethality, whereas mice selectively lacking the 110 kDa PARG isoform (PARG(110)(-/-)) develop normally. We used PARG(110)(-/-) mice to evaluate the importance of PAR catabolism to postischemic brain damage. Poly(ADP-ribose) contents were higher in the brain tissue of PARG(110)(-/-) than PARG(110)(+/+) mice, both under basal conditions and after PARP activation. Distal middle cerebral artery occlusion caused higher increase of brain PAR levels and larger infarct volumes in PARG(110)(-/-) mice than in wild-type counterparts. Of note, the brain of PARG(110)(-/-) mice showed reduced heat-shock protein (HSP)-70 and increased cyclooxygenase-2 expression under both control and ischemic conditions. No differences were detected in brain expression/activation of procaspase-3, PARP-1, Akt, HSP-25 and interleukin-1beta. Our findings show that PAR accumulation worsens ischemic brain injury, and highlight the therapeutic potential of strategies capable of maintaining PAR homeostasis.
 ...
PMID:Poly(ADP-ribose) accumulation and enhancement of postischemic brain damage in 110-kDa poly(ADP-ribose) glycohydrolase null mice. 1617 11

Protein ADP ribosylation catalyzed by cellular poly(ADP-ribose) polymerases (PARPs) and tankyrases modulates chromatin structure, telomere elongation, DNA repair, and the transcription of genes involved in stress resistance, hormone responses, and immunity. Using Drosophila genetic tools, we characterize the expression and function of poly(ADP-ribose) glycohydrolase (PARG), the primary enzyme responsible for degrading protein-bound ADP-ribose moieties. Strongly increasing or decreasing PARG levels mimics the effects of Parp mutation, supporting PARG's postulated roles in vivo both in removing ADP-ribose adducts and in facilitating multiple activity cycles by individual PARP molecules. PARP is largely absent from euchromatin in PARG mutants, but accumulates in large nuclear bodies that may be involved in protein recycling. Reducing the level of either PARG or the silencing protein SIR2 weakens copia transcriptional repression. In the absence of PARG, SIR2 is mislocalized and hypermodified. We propose that PARP and PARG promote chromatin silencing at least in part by regulating the localization and function of SIR2 and possibly other nuclear proteins.
 ...
PMID:Drosophila poly(ADP-ribose) glycohydrolase mediates chromatin structure and SIR2-dependent silencing. 1621 73

ADP-ribosylation is a post-translational modification resulting from transfer of the ADP-ribose moiety of NAD to protein. Mammalian cells contain mono-ADP-ribosyltransferases that catalyze the formation of ADP-ribose-(arginine) protein, which can be cleaved by a 39-kDa ADP-ribose-(arginine) protein hydrolase (ARH1), resulting in release of free ADP-ribose and regeneration of unmodified protein. Enzymes involved in poly(ADP-ribosylation) participate in several critical physiological processes, including DNA repair, cellular differentiation, and carcinogenesis. Multiple poly(ADP-ribose) polymerases have been identified in the human genome, but there is only one known poly(ADP-ribose) glycohydrolase (PARG), a 111-kDa protein that degrades the (ADP-ribose) polymer to ADP-ribose. We report here the identification of an ARH1-like protein, termed poly(ADP-ribose) hydrolase or ARH3, which exhibited PARG activity, generating ADP-ribose from poly-(ADP-ribose), but did not hydrolyze ADP-ribose-arginine, -cysteine, -diphthamide, or -asparagine bonds. The 39-kDa ARH3 shares amino acid sequence identity with both ARH1 and the catalytic domain of PARG. ARH3 activity, like that of ARH1, was enhanced by Mg(2+). Critical vicinal acidic amino acids in ARH3, identified by mutagenesis (Asp(77) and Asp(78)), are located in a region similar to that required for activity in ARH1 but different from the location of the critical vicinal glutamates in the PARG catalytic site. All findings are consistent with the conclusion that ARH3 has PARG activity but is structurally unrelated to PARG.
 ...
PMID:Identification and characterization of a mammalian 39-kDa poly(ADP-ribose) glycohydrolase. 1627 11

Disruption of poly(ADP-ribose) polymerase (PARP) pathways by inhibitors of PARP catalytic domain has been shown to increase the anti-tumour activity of temozolomide (TMZ). Since PARP is inhibited by poly(ADP)ribosylation, herein we tested whether inhibition of poly(ADP-ribose) glycohydrolase (PARG) might enhance TMZ efficacy. The PARG inhibitor N-bis-(3-phenyl-propyl)9-oxo-fluorene-2,7-diamide (GPI 16552) was administered in combination with TMZ to mice injected subcutaneously or intracranially with B16 melanoma cells. The ability of treatment to reduce melanoma metastatic spreading and invasion of the extracellular matrix was also tested. The results indicated that combined treatment with GPI 16552 and TMZ significantly reduced melanoma growth, increased life-span of mice bearing tumour at the CNS site, and decreased the ability of melanoma cells to form lung metastases and to invade the extracellular matrix. In conclusion, PARG inhibition represents an alternative strategy to enhance TMZ efficacy against melanoma in peripheral as well as at CNS site.
 ...
PMID:Poly(ADP-ribose) glycohydrolase inhibitor as chemosensitiser of malignant melanoma for temozolomide. 1628 62

Poly(ADP-ribosyl)ation is a very early cellular response to DNA damage. Poly(ADP-ribose) (PAR) accumulation is transient since PAR is rapidly hydrolyzed by poly(ADP-ribose) glycohydrolase (PARG). PARG may play a prominent role in DNA damage response and repair by removing PAR from modified proteins including PARP-1. Using living cells, we provide evidence that in response to DNA damage induced by gamma-irradiation the cytoplasmic 103 kDa PARG isoform translocates into the nucleus. We further observed that the nuclear GFP-hPARG110 enzyme relocalizes to the cytoplasm in response to DNA damage. Using different GFP-PARG fusion proteins specific for the nuclear and cytoplasmic forms, we demonstrate their dynamic distribution between cytoplasm and nucleoplasm and a high mobility of major PARG isoforms by fluorescence recovery after photobleaching (FRAP). The dynamic relocation of all PARG isoforms presented in this report reveals a novel biological mechanism by which PARG could be involved in DNA damage response.
 ...
PMID:Dynamic relocation of poly(ADP-ribose) glycohydrolase isoforms during radiation-induced DNA damage. 1646 Aug 18

The silent information regulator 2 (Sir2) family of NAD-dependent N-acetyl-protein deacetylases participates in the regulation of gene silencing, chromatin structure, and longevity. In the Sir2-catalyzed reaction, the acetyl moiety of N-acetyl-histone is transferred to the ADP-ribose of NAD, yielding O-acetyl-ADP-ribose and nicotinamide. We hypothesized that, if O-acetyl-ADP-ribose were an important signaling molecule, a specific hydrolase would cleave the (O-acetyl)-(ADP-ribose) linkage. We report here that the poly(ADP-ribose) glycohydrolase ARH3 hydrolyzed O-acetyl-ADP-ribose to produce ADP-ribose in a time- and Mg(2+)-dependent reaction and thus could participate in two signaling pathways. This O-acetyl-ADP-ribose hydrolase belongs to a family of three structurally related 39-kDa ADP-ribose-binding proteins (ARH1-ARH3). ARH1 was reported to hydrolyze ADP-ribosylarginine, whereas ARH3 degraded poly(ADP-ribose). ARH3-catalyzed generation of ADP-ribose from O-acetyl-ADP-ribose was significantly faster than from poly(ADP-ribose). Like the degradation of poly(ADP-ribose) by ARH3, hydrolysis of O-acetyl-ADP-ribose was abolished by replacement of the vicinal aspartates at positions 77 and 78 of ARH3 with asparagine. The rate of O-acetyl-ADP-ribose hydrolysis by recombinant ARH3 was 250-fold that observed with ARH1; ARH2 and poly(ADP-ribose) glycohydrolase were inactive. All data support the conclusion that the Sir2 reaction product O-acetyl-ADP-ribose is degraded by ARH3.
 ...
PMID:The 39-kDa poly(ADP-ribose) glycohydrolase ARH3 hydrolyzes O-acetyl-ADP-ribose, a product of the Sir2 family of acetyl-histone deacetylases. 1707 46


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>