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.

Histone H1 Poly[ADP]-Ribosylation Regulates the Chromatin Alterations Required for Learning Consolidation

“…Our gene expression analysis in the hippocampus after OR training demonstrated the increase in NF-B and CREB gene targets and, in both cases, training-induced NF-B-and CREB-dependent gene expression required of PARP-1 activation. It is well known that PARP-1 works as a coactivator of NF-B in some cell types (Aguilar-Quesada et al, 2007), although to our knowledge this is the first description of PARP-1 and CREB transcriptional cooperation.…”

Poly(ADP-ribose)-dependent regulation of Snail1 protein stability

“…Involvement of PARP-1 on Snail1 activation and E-cadherin expression Previous results have shown that PARP-1 is implicated in the regulation of transcription at different levels (Kim et al, 2005), and its ability to modulate transcription factors involved in tumor development and angiogenesis has been repeatedly reported (Aguilar-Quesada et al, 2007). In the present study, we have analyzed the involvement of PARP-1 and its activity on the modulation of Snail1, a key transcription factor involved in cell migration during development and metastasis.…”

The poly(ADP-ribose) polymerase-1 inhibitor 3-aminobenzamide suppresses cell growth and migration, enhancing suppressive effects of cisplatin in osteosarcoma cells

“…As pArp-1 actively participates in DnA repair, pArp-1 inhibitors have been applied in cancer treatment either alone or in combination with DnA-damaging agents (14). several studies have demonstrated that pharmacological inhibition or genetic ablation of pArp-1 not only provided remarkable protection from tissue injury in various oxidative stress-related disease models but also resulted in a clear beneficial outcome in the treatment of cancer (15). In certain types of tumors including lung cancer, colon carcinoma and cervical cancer, pArp-1 inhibition was shown to be an effective means of enhancing tumor sensitivity to radiation and chemotherapy (16)(17)(18)(19), also pArp inhibitor could be used as single agents to selectively kill cancers defective in DnA repair, specifically cancers with mutations in the breast cancerassociated genes (BrcA1 and BrcA2) (20,21).…”