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

Abstract

The basic leucine zipper (bZIP) 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 does it promote 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.

NRF2 negatively regulates primary ciliogenesis and hedgehog signaling

“…Biotin-DNA pull-down was performed as reported previously [60]. In brief, cells were lysed in RIPA buffer containing 1 mM DTT, 1 mM phenylmethylsulfonyl fluoride (PMSF), and 1% protease inhibitor cocktail (Sigma-Aldrich).…”

Poly(ADP-ribose) polymerases as modulators of mitochondrial activity

“…Furthermore, PARP-1 was also shown to act as a transcriptional coactivator for NRF-2. PARP-1 binds NRF2 indirectly through the adaptor protein Maf and upregulates the its transcriptional activity [58]. It is important to note that the interactions between PARP-1 and NRF-1/2 are independent of the enzymatic activation of PARP-1, which can be crucial in cells recovering from sublethal oxidative injury (Box 1)…”

“…Some of these pathways are independent of PARylation (e.g., NRFs [57,58]), and are hence capable of preserving mitochondrial activity under stress conditions. These feedforward pathways might be important for cells to recover from sublethal PARP-mediated stress situations [42,49,50].…”

Nrf2 promotes survival following exposure to ionizing radiation

“…Loss of BRCA1 (or BRCA2) in cancer can be exploited by targeting PARP1, a facilitator of DNA repair [67]. Recently, Wu et al [68] found that PARP1 interacts directly with small Maf proteins, NRF2’s heterodimeric partners, and that this complex augments Nrf2’s ARE-specific DNA binding, thereby enhancing Nrf2-dependent gene transcription. Thus, one may hypothesize that the therapeutic efficacy obtained by molecular targeting of PARP1 in cancer could be due in part to suppression of Nrf2-mediated DNA repair.…”