title: Poly(ADP-ribose) polymerase-1 modulates Nrf2-dependent transcription.
abstract: The basic leucine zipper transcription factor Nrf2 has emerged as a master regulator of intracellular redox homeostasis by controlling the expression of a battery of redox-balancing antioxidants and phase II detoxification enzymes. Under oxidative stress conditions, Nrf2 is induced at the protein level through redox-sensitive modifications on critical cysteine residues in Keap1, a component of an E3 ubiquitin ligase complex that targets Nrf2 for proteasomal degradation. Poly(ADP-ribose) polymerase-1 (PARP-1) is historically known to function in DNA damage detection and repair; however, recently PARP-1 has been shown to play an important role in other biochemical activities, such as DNA methylation and imprinting, insulator activity, chromosome organization, and transcriptional regulation. The exact role of PARP-1 in transcription modulation and the underlying mechanisms remain poorly defined. In this study, we report that PARP-1 forms complexes with the antioxidant response element (ARE) within the promoter region of Nrf2 target genes and upregulates the transcriptional activity of Nrf2. Interestingly, PARP-1 neither physically interacts with Nrf2 nor promotes the expression of Nrf2. In addition, PARP-1 does not target Nrf2 for poly(ADP-ribosyl)ation. Instead, PARP-1 interacts directly with small Maf proteins and the ARE of Nrf2 target genes, which augments ARE-specific DNA-binding of Nrf2 and enhances the transcription of Nrf2 target genes. Collectively, these results suggest that PARP-1 serves as a transcriptional coactivator, upregulating the transcriptional activity of Nrf2 by enhancing the interaction among Nrf2, MafG, and the ARE.
authors.affiliation: Department of Pharmacology & Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ 85721, USA.
authors.forename: Tongde
authors.initials: T
authors.lastname: Wu
authors.affiliation: Department of Pharmacology & Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ 85721, USA.
authors.forename: Xiao-Jun
authors.initials: XJ
authors.lastname: Wang
authors.affiliation: Department of Pharmacology & Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ 85721, USA.
authors.forename: Wang
authors.initials: W
authors.lastname: Tian
authors.affiliation: Department of Pharmacology & Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ 85721, USA.
authors.forename: Melba C
authors.initials: MC
authors.lastname: Jaramillo
authors.affiliation: Department of Pharmacology & Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ 85721, USA.
authors.forename: Alexandria
authors.initials: A
authors.lastname: Lau
authors.affiliation: Department of Pharmacology & Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ 85721, USA; Arizona Cancer Center, University of Arizona, Tucson, AZ 85724, USA. Electronic address: dzhang@pharmacy.arizona.edu.
authors.forename: Donna D
authors.initials: DD
authors.lastname: Zhang
mesh_terms: D000818:Animals; D061745:Antioxidant Response Elements; D045744:Cell Line, Tumor; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D051259:MafG Transcription Factor / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000235:genetics* / Q000378:metabolism; D010084:Oxidation-Reduction; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: C103944:MAFG protein, human; D051259:MafG Transcription Factor; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D012097:Repressor Proteins; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases
keywords: ARE; Free radicals; Maf; Nrf2; PARP-1; Transcriptional coactivator