Structure and function of poly(ADP-ribose) polymerase-1: Role in oxidative stress-related pathologies

Research output: Contribution to journalArticle

119 Citations (Scopus)

Abstract

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 NFκB 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).

Original languageEnglish
Pages (from-to)209-214
Number of pages6
JournalCurrent Vascular Pharmacology
Volume3
Issue number3
DOIs
Publication statusPublished - Jul 2005

Fingerprint

Oxidative Stress
Pathology
Poly(ADP-ribose) Polymerases
Adenosine Diphosphate
DNA Damage
Polymers
Cell Death
Apoptosis Inducing Factor
Adenosine Diphosphate Ribose
Apoptosis
DNA Repair Enzymes
Poly Adenosine Diphosphate Ribose
Myocardial Reperfusion
DNA Breaks
Deoxyribonucleases
Poly (ADP-Ribose) Polymerase-1
Glycoside Hydrolases
Uveitis
Transcription Factor AP-1
Nitric Oxide Synthase Type II

Keywords

  • Apoptosis
  • Cytotoxicity
  • DNA damage
  • Necrosis
  • Peroxynitrite
  • Poly(ADP-ribose) polymerase

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Pharmacology

Cite this

Structure and function of poly(ADP-ribose) polymerase-1 : Role in oxidative stress-related pathologies. / Virag, L.

In: Current Vascular Pharmacology, Vol. 3, No. 3, 07.2005, p. 209-214.

Research output: Contribution to journalArticle

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