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Free Radic Biol Med. 2014 Feb;67:69-80. doi: 10.1016/j.freeradbiomed.2013.10.806. Epub 2013 Oct 17.

Poly(ADP-ribose) polymerase-1 modulates Nrf2-dependent transcription.

Author information

1
Department of Pharmacology & Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ 85721, USA.
2
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.

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.

KEYWORDS:

ARE; Free radicals; Maf; Nrf2; PARP-1; Transcriptional coactivator

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