Modulation of Transcription by PARP-1: Consequences in Carcinogenesis and Inflammation

• Published in: Current medicinal chemistry Vol. 14; no. 11; pp. 1179 - 1187
• Main Authors: AGUILAR-QUESADA, R, MUNOZ-GAMEZ, J. A, MARTIN-OLIVA, D, PERALTA-LEAL, A, QUILES-PEREZ, R, RODRIGUEZ -VARGAS, J. M, RUIZ DE ALMODOVAR, M, CONDE, C, RUIZ-EXTREMERA, A, OLIVER, F. J
• Format: Journal Article
• Language: English
• Published: Schiphol Bentham Science Publishers Ltd 01.05.2007; Bentham Science
• Subjects: Adenosine diphosphate; Biological and medical sciences; Carcinogenesis; Carcinogenesis, carcinogens and anticarcinogens; Chemical agents; Deoxyribonucleic acid; DNA; Fundamental and applied biological sciences. Psychology; Histones - metabolism; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - physiology; Inflammation; Inflammation - physiopathology; Medical sciences; Models, Biological; Molecular and cellular biology; Mortality; Neoplasms - etiology; NF-kappa B - physiology; Oxidative stress; Oxidative Stress - physiology; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerases - physiology; Polymers; Proteins; Transcription Factors - metabolism; Transcription, Genetic - drug effects; Translocation; Tumors; Oxidative stress; Transcription; Enzyme; Transferases; Glycosyltransferases; Inflammation; Carcinogenesis; Posttranslational modification; NAD; Cell death; Modulation; ADP-ribosyltransferase; Mechanism of action; Pentosyltransferases; Apoptosis
• ISSN: 0929-8673; 1875-533X
• DOI: 10.2174/092986707780597998

Post-translational modification of proteins by poly(ADP-ribosyl)ation is involved in the regulation of a number of biological functions. While an 18 member superfamily of poly(ADP-ribose) polymerases (PARP)s has been described PARP-1 accounts for more than 90% of the poly(ADP-ribosyl)ating capacity of the cells. PARP-1 act as a DNA nick sensor and is activated by DNA breaks to cleave NAD(+) into nicotinamide and ADP-ribose to synthesize long branching poly(ADP-ribose) polymers (PAR) covalently attached to nuclear acceptor proteins. Whereas activation of PARP-1 by mild genotoxic stimuli facilitate DNA repair and cell survival, severe DNA damage triggers different pathways of cell death including PARP-mediated cell death through the translocation of apoptosis inducing factor (AIF) from the mitochondria to the nucleus. PAR and PARP-1 have also been described as having a function in transcriptional regulation through their ability to modify chromatin-associated proteins and as a cofactor of different transcription factors, most notably NF-κB and AP-1. Pharmacological inhibition or genetic ablation of PARP-1 not only provided remarkable protection from tissue injury in various oxidative stress-related disease models but it result in a clear benefit in the treatment of cancer by different mechanisms including selective killing of homologous recombination-deficient tumor cells, down regulation of tumor-related gene expression and decrease in the apoptotic threshold in the co-treatment with chemo and radiotherapy. We will summarize in this review the current findings and concepts for the role of PARP-1 and poly(ADP-ribosyl)ation in the regulation of transcription, oxidative stress and carcinogenesis.