| Structure and function of poly(ADP-ribose) polymerase-1: role in oxidative stress-related pathologies. | |
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MedLine Citation:
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PMID: 16026317 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Poly(ADP-ribosyl) ation is a reversible post-translational protein modification implicated in the regulation of a number of biological functions. Whereas an 18 member superfamily of poly(ADP-ribose) polymerase (PARP) enzymes synthesize poly(ADP-ribose) (PAR), a single protein, PAR glycohydrolase (PARG) is responsible for the catabolism of the polymer. PARP-1 accounts for more than 90% of the poly(ADP-ribosyl)ating capacity of the cells. PARP-1 activated by DNA breaks cleaves NAD(+) into nicotinamide and ADP-ribose and uses the latter to synthesize long branching PAR polymers covalently attached to acceptor proteins including histones, DNA repair enzymes, transcription factors and PARP-1. Whereas activation of PARP-1 by mild genotoxic stimuli may facilitate DNA repair and cell survival, irreparable DNA damage triggers apoptotic or necrotic cell death. In apoptosis, early PARP activation may assist the apoptotic cascade [e.g. by stabilizing p53, by mediating the translocation of apoptosis inducing factor (AIF) from the mitochondria to the nucleus or by inhibiting early activation of DNases]. In most severe oxidative stress situations, excessive DNA damage causes over activation of PARP-1, which incapacitates the apoptotic machinery and switches the mode of cell death from apoptosis to necrosis. Besides serving as a cytotoxic mediator, PARP-1 is also involved in transcriptional regulation, most notably in the NF kappaB and AP-1 driven expression of inflammatory mediators. Pharmacological inhibition or genetic ablation of PARP-1 provided remarkable protection from tissue injury in various oxidative stress-related disease models ranging from stroke, diabetes, diabetic endothelial dysfunction, myocardial ischemia-reperfusion, shock, Parkinson's disease, arthritis, colitis to dermatitis and uveitis. These beneficial effects are attributed to inhibition of the PARP-1 mediated suicidal pathway and to reduced expression of inflammatory cytokines and other mediators (e.g. inducible nitric oxide synthase). |
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Authors:
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László Virág |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't; Review |
Journal Detail:
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Title: Current vascular pharmacology Volume: 3 ISSN: 1570-1611 ISO Abbreviation: Curr Vasc Pharmacol Publication Date: 2005 Jul |
Date Detail:
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Created Date: 2005-07-19 Completed Date: 2005-08-26 Revised Date: 2006-11-15 |
Medline Journal Info:
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Nlm Unique ID: 101157208 Medline TA: Curr Vasc Pharmacol Country: United Arab Emirates |
Other Details:
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Languages: eng Pagination: 209-14 Citation Subset: IM |
Affiliation:
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Department of Medical Chemistry, Research Center for Molecular Medicine, Medical and Health Science Center, University of Debrecen, Bem tér 18/B, Hungary. lvirag@dote.hu |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Apoptosis Enzyme Inhibitors / pharmacology Glycoside Hydrolases / metabolism* Humans Necrosis Oxidative Stress* Poly Adenosine Diphosphate Ribose / metabolism* Poly(ADP-ribose) Polymerases / antagonists & inhibitors, metabolism* |
| Chemical | |
Reg. No./Substance:
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0/Enzyme Inhibitors; 26656-46-2/Poly Adenosine Diphosphate Ribose; EC 2.4.2.30/Poly(ADP-ribose) Polymerases; EC 3.2.1.-/Glycoside Hydrolases; EC 3.2.1.143/poly ADP-ribose glycohydrolase |
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