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Current Medicinal Chemistry


ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

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

Author(s): R. Aguilar-Quesada, J. A. Munoz-Gamez, D. Martin-Oliva, A. Peralta-Leal, R. Quiles-Perez, J. M. Rodriguez-Vargas, M. Ruiz de Almodovar, C. Conde, A. Ruiz-Extremera and F. J. Oliver

Volume 14 , Issue 11 , 2007

Page: [1179 - 1187] Pages: 9

DOI: 10.2174/092986707780597998

Price: $65


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.

Keywords: zinc finger DNA-binding domain, double-strand breaks, DNA repair, Histone-Modifying Activity, CXCL1 promoter, Inflammatory Diseases

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