title: SETD6 is a negative regulator of oxidative stress response.
abstract: The protein methyltransferase SETD6 is a key regulator of proliferation and inflammatory processes. However, the role of SETD6 in the regulation of additional cell signaling pathways has not been well studied. Here we show that SETD6 is a negative regulator of the oxidative stress response. Depletion of SETD6 from cells results in elevated Nrf2 levels and a significant increase in Nrf2 antioxidant target gene expression. Using proteomic tools, we uncovered a novel interaction between SETD6 and the oxidative stress sensor DJ1, a protein required for Nrf2-dependent transcription of antioxidant target genes. We show that SETD6 binds DJ1 both in-vitro and in cells but does not methylate DJ1. Under basal conditions, SETD6 and DJ1 are associated at chromatin. Through this interaction, SETD6 inhibits DJ1 activity, which in turn leads to the repression of Nrf2-dependent transcription. In response to oxidative stress, the transcription of Nrf2 antioxidant genes increases. We here show that under this condition, SETD6 mRNA and protein levels are reduced, leading to elevation in Nrf2 expression level and to a weaken interaction between SETD6 and DJ1 at chromatin. Taken together, these findings demonstrate that SETD6 negatively regulates the Nrf2-mediated oxidative stress response through a physical and catalytically independent interaction with DJ1 at chromatin.
authors.affiliation: The Shraga Segal Department of Microbiology, Immunology and Genetics, Israel; National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, P.O.B. 653, Be'er Sheva 84105, Israel.
authors.forename: Ayelet
authors.initials: A
authors.lastname: Chen
authors.affiliation: The Shraga Segal Department of Microbiology, Immunology and Genetics, Israel; National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, P.O.B. 653, Be'er Sheva 84105, Israel.
authors.forename: Michal
authors.initials: M
authors.lastname: Feldman
authors.affiliation: The Shraga Segal Department of Microbiology, Immunology and Genetics, Israel; National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, P.O.B. 653, Be'er Sheva 84105, Israel.
authors.forename: Zlata
authors.initials: Z
authors.lastname: Vershinin
authors.affiliation: The Shraga Segal Department of Microbiology, Immunology and Genetics, Israel; National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, P.O.B. 653, Be'er Sheva 84105, Israel. Electronic address: ledan@post.bgu.ac.il.
authors.forename: Dan
authors.initials: D
authors.lastname: Levy
mesh_terms: D000975:Antioxidants / Q000378:metabolism; D002460:Cell Line; D002843:Chromatin / Q000235:genetics; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000235:genetics* / Q000378:metabolism; D015513:Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D018384:Oxidative Stress / Q000235:genetics*; D000071617:Protein Deglycase DJ-1; D011496:Protein Methyltransferases / Q000235:genetics* / Q000378:metabolism; D040901:Proteomics; D015398:Signal Transduction / Q000235:genetics
chemical_list: D000975:Antioxidants; D002843:Chromatin; D047908:Intracellular Signaling Peptides and Proteins; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D015513:Oncogene Proteins; D011496:Protein Methyltransferases; C562071:SETD6 protein, human; C105131:PARK7 protein, human; D000071617:Protein Deglycase DJ-1
keywords: DJ1; Oxidative stress; SETD6