title: Modulation of transcription by PARP-1: consequences in carcinogenesis and inflammation.
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-kappaB 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.
authors.affiliation: Instituto de Parasitología y Biomedicina López Neyra, CSIC, Granada, Spain.
authors.forename: R
authors.initials: R
authors.lastname: Aguilar-Quesada
authors.forename: J A
authors.initials: JA
authors.lastname: Muñoz-Gámez
authors.forename: D
authors.initials: D
authors.lastname: Martín-Oliva
authors.forename: A
authors.initials: A
authors.lastname: Peralta-Leal
authors.forename: R
authors.initials: R
authors.lastname: Quiles-Pérez
authors.forename: J M
authors.initials: JM
authors.lastname: Rodríguez-Vargas
authors.forename: M
authors.initials: M
authors.lastname: Ruiz de Almodóvar
authors.forename: C
authors.initials: C
authors.lastname: Conde
authors.forename: A
authors.initials: A
authors.lastname: Ruiz-Extremera
authors.forename: F J
authors.initials: FJ
authors.lastname: Oliver
mesh_terms: D006657:Histones / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology; D007249:Inflammation / Q000503:physiopathology; D008954:Models, Biological; D016328:NF-kappa B / Q000502:physiology; D009369:Neoplasms / Q000209:etiology; D018384:Oxidative Stress / Q000502:physiology; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*
chemical_list: D006657:Histones; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016328:NF-kappa B; D014157:Transcription Factors; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases