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

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

Volume: 14 Issue: 11

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

Affiliation:

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

Abstract: 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.

Cite this article as:

Aguilar-Quesada R., Munoz-Gamez A. J., Martin-Oliva D., Peralta-Leal A., Quiles-Perez R., Rodriguez-Vargas M. J., Ruiz de Almodovar M., Conde C., Ruiz-Extremera A. and Oliver J. F., Modulation of Transcription by PARP-1: Consequences in Carcinogenesis and Inflammation, Current Medicinal Chemistry 2007; 14 (11) . https://dx.doi.org/10.2174/092986707780597998