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Poly(ADP-ribose) polymerase-1 modulates Nrf2-dependent transcription
Tongde Wu1, Xiao-Jun Wang1, Wang Tian1
1Department of Pharmacology & Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ 85721, USA.
Free Radical Biology & Medicine
|October 22, 2013
Summary
Poly(ADP-ribose) polymerase-1 (PARP-1) enhances the activity of the transcription factor Nrf2, a key regulator of cellular defense. PARP-1 acts as a coactivator, boosting Nrf2
Area of Science:
- Molecular Biology
- Cellular Biology
- Biochemistry
Background:
- Nuclear factor erythroid 2-related factor 2 (Nrf2) is a master regulator of cellular redox homeostasis and detoxification.
- Poly(ADP-ribose) polymerase-1 (PARP-1) is known for DNA repair but its role in transcription is less defined.
- Keap1 regulates Nrf2 stability via ubiquitination, particularly under oxidative stress.
Purpose of the Study:
- To elucidate the precise role and mechanism of PARP-1 in modulating Nrf2 transcriptional activity.
- To investigate the interaction of PARP-1 with Nrf2 target genes and regulatory proteins.
- To determine if PARP-1 influences Nrf2 expression or stability.
Main Methods:
- Chromatin immunoprecipitation to detect PARP-1 binding to the antioxidant response element (ARE) of Nrf2 target genes.
- Co-immunoprecipitation assays to assess protein-protein interactions.
- Reporter gene assays to measure transcriptional activity.
- Western blotting to analyze protein levels.
Main Results:
- PARP-1 binds to the ARE in the promoter regions of Nrf2 target genes.
- PARP-1 directly interacts with small Maf proteins, not Nrf2.
- PARP-1 enhances Nrf2's ARE-specific DNA-binding and transcriptional activity without affecting Nrf2 expression or stability.
- PARP-1 does not poly(ADP-ribosyl)ate Nrf2.
Conclusions:
- PARP-1 functions as a transcriptional coactivator for Nrf2.
- PARP-1 upregulates Nrf2 target gene transcription by facilitating the interaction between Nrf2, MafG, and the ARE.
- These findings reveal a novel mechanism by which PARP-1 regulates cellular defense pathways.
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