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

---

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

PARP-1 is the most abundantly expressed member of a family of proteins that catalyze the transfer of ADP-ribose units from NAD+ to target proteins. Herein, we describe previously uncharacterized nucleosome binding properties of PARP-1 that promote the formation of compact, transcriptionally repressed chromatin structures. PARP-1 binds in a specific manner to nucleosomes and modulates chromatin structure through NAD+-dependent automodification, without modifying core histones or promoting the disassembly of nucleosomes. The automodification activity of PARP-1 is potently stimulated by nucleosomes, causing the release of PARP-1 from chromatin. The NAD+-dependent activities of PARP-1 are reversed by PARG, a poly(ADP-ribose) glycohydrolase, and are inhibited by ATP. In vivo, PARP-1 incorporation is associated with transcriptionally repressed chromatin domains that are spatially distinct from both histone H1-repressed domains and actively transcribed regions. Thus, PARP-1 functions both as a structural component of chromatin and a modulator of chromatin structure through its intrinsic enzymatic activity.
...
PMID:NAD+-dependent modulation of chromatin structure and transcription by nucleosome binding properties of PARP-1. 1560 68

Unlike poly(ADP-ribose) polymerase-1 (PARP-1), poly(ADP-ribose) glycohydrolase (PARG) has long been a difficult protein to study. However, the complete absence of PARG activity was recently characterized in mice via disruption of the murine PARG gene. As expected, PARG is critical for the maintenance of steady-state poly(ADP-ribose) levels. But surprisingly, the disruption of PARG led to embryonic lethality and increased susceptibility to mild cell stress. Therefore, the protective role of PARG and its involvement in development indicate that these roads to viability go through PARG.
...
PMID:The road to survival goes through PARG. 1572 27

The importance of poly(ADP-ribose) metabolism in the maintenance of genomic integrity following genotoxic stress has long been firmly established. Poly(ADP-ribose) polymerase-1 (PARP-1) and its catabolic counterpart, poly(ADP-ribose) glycohydrolase (PARG) play major roles in the modulation of cell responses to genotoxic stress. Recent discoveries of a number of other enzymes with poly(ADP-ribose) polymerase activity have established poly(ADP-ribosyl)ation as a general biological mechanism in higher eukaryotic cells that not only promotes cellular recovery from genotoxic stress and eliminates severely damaged cells from the organism, but also ensures accurate transmission of genetic information during cell division. Additionally, emerging data suggest the involvement of poly(ADP-ribosyl)ation in the regulation of intracellular trafficking, memory formation and other cellular functions. In this brief review on PARP and PARG enzymes, emphasis is placed on PARP-1, the best understood member of the PARP family and on the relationship of poly(ADP-ribosyl)ation to cancer and other diseases of aging.
...
PMID:Poly(ADP-ribose) polymerases: managing genome stability. 1574 66

Poly (ADP-ribosyl)ation, an early post-translational modification in response to DNA damage, is catalyzed by poly (ADP-ribose) polymerase (PARP-1) and catabolized by poly(ADP-ribose) glycohydrolase (PARG). The aim of this study was to investigate the role of PARG on the modulation of the inflammatory response caused by splanchnic ischemia and reperfusion. SAO shock in rats and wild-type (WT) mice was associated with a significant neutrophil infiltration in the ileum and production of tumor necrosis factor-alpha (TNF-alpha). Reperfused ileum tissue sections from SAO-shocked WT mice and rats showed positive staining for P-selectin and ICAM-1 localized mainly in the vascular endothelial cells. Genetic disruption of the PARG gene in mice or pharmacological inhibition of PARG by PARG inhibitors significantly improved the histological status of the reperfused tissues associated with reduced expression of P-selectin and ICAM-1, neutrophil infiltration into the reperfused intestine, and TNF-alpha production. These results suggest that PARG activity modulates the inflammatory response in ischemia/reperfusion and participates in end (target) organ damage under these conditions.
...
PMID:PARG activity mediates intestinal injury induced by splanchnic artery occlusion and reperfusion. 1579 Oct 6

Poly(ADP-ribose) glycohydrolase (PARG) is a catabolic enzyme that cleaves ADP-ribose polymers formed by members of the PARP family of enzymes. Despite its discovery and subsequent partial purification in the 1970s and the cloning of its single gene in the late 1990s, little is known about the role of PARG in cell function. Because of its low abundance within cells and its extreme sensitivity to proteases, PARG has been difficult to study. The existence of several PARG isoforms with different subcellular localizations is still debated today after more than 30 years of intensive research. In this article, we want to summarize and discuss the current knowledge related to PARG, its different forms and subcellular distribution. We also examine the possible biological roles of PARG in modulating chromatin structure, transcription, DNA repair and apoptosis.
...
PMID:Regulation of poly(ADP-ribose) metabolism by poly(ADP-ribose) glycohydrolase: where and when? 1586 99

Carcinogenesis involves multiple steps and pathways with functional alterations in a variety of genes. There is accumulating evidence that a deficiency of poly(ADP-ribose) polymerase (PARP)-1 leads to DNA repair defects, genomic instability, failure of induction of cell death and modulation of gene transcription. PARP-1 also supports the growth of tumor cells in certain situations. Genetic analyses of the PARP-1 gene have demonstrated alterations in neoplasms, and a mutation affecting the conserved amino acid E251 in germ cell tumors, as well as an association of a single-nucleotide polymorphism V762A with risk of prostate cancer. Recent development of a selective inhibitor of poly(ADP-ribose) glycohydrolase (PARG), the enzyme primarily responsible for degradation of poly(ADP-ribose), and PARG-deficient animals should facilitate studies of the relationship of poly(ADP-ribose) with carcinogenesis. Inhibitors of PARP have also suggested roles in the pathogenesis of autoimmune disease, and a promoter haplotype of PARP-1 confers a higher risk of rheumatoid arthritis. Further analysis of PARP-1, PARG and other PARP family genes should extend our understanding of the pathogenesis of cancer and autoimmune diseases. Furthermore, there is potential for sensitization to chemo- and radiation therapy of cancers as well as the treatment of autoimmune disease with development of stronger PARP inhibitors.
...
PMID:Poly(ADP-ribosyl)ation in relation to cancer and autoimmune disease. 1586 2

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

Tannins are plant-derived water-soluble polyphenols with wide-ranging biological activities. The mechanisms underlying the anti-inflammatory effect of tannins are not fully understood and may be the result of inhibition of poly(ADP-ribose) (PAR) glycohydrolase (PARG), the main catabolic enzyme of PAR metabolism. Therefore, we set out to investigate the mechanism of the anti-inflammatory effect of gallotannin (GT) in A549 cells with special regard to the role of poly(ADP-ribosyl)ation. Using an inflammation-focused low-density array and reverse transcription-polymerase chain reaction, we found that GT suppressed the expression of most cytokines and chemokines in cytokine-stimulated A549 cells, whereas the PARP inhibitor PJ-34 only inhibited few transcripts. Activation of the transcription factors, nuclear factor kappaB (NF-kappaB) and activator protein 1 (AP-1), was blocked by GT, whereas PJ-34 only suppressed NF-kappaB activation but not AP-1 activation. GT also inhibited IkappaB phosphorylation and nuclear translocation of NF-kappaB, but PJ-34 had no effect on these upstream events. In the AP-1 pathway, GT treatment, even in the absence of cytokines, caused maximal phosphorylation of c-Jun N-terminal kinase and c-Jun. GT also caused a low-level phosphorylation of p38, extracellular signal-regulated kinases 1 and 2, activating transcription factor2, and cAMP-response element-binding protein but inhibited cytokine-induced phosphorylation of these kinases and transcription factors. GT inhibited protein phosphatases 1 and 2A, which may explain the increased phosphorylation of mitogen-activated protein kinase and their substrates. GT exerted potent antioxidant effect but failed to cause PAR accumulation. In summary, the potent inhibitory effects of GT on the transcription of cytokine and chemokine genes are probably not related to PARG inhibition. Inhibition of AP-1 activation and upstream signaling events may be responsible for the effects of GT.
...
PMID:Gallotannin inhibits the expression of chemokines and inflammatory cytokines in A549 cells. 1597 37


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

---