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MCB Accepts, published online ahead of print on 21 August 2006
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Mol. Cell. Biol. doi:10.1128/MCB.00700-06
Copyright (c) 2006, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

BRG1 Interacts with Nrf2 to Selectively Mediate HO-1 Induction in Response to Oxidative Stress

Jianyong Zhang, Tsutomu Ohta, Atsushi Maruyama, Tomonori Hosoya, Keizo Nishikawa, Jonathan M. Maher, Shigeki Shibahara, Ken Itoh*, and Masayuki Yamamoto*

ERATO Environmental Response Project and Institute of Basic Medical Sciences and Center for Tsukuba Advanced Research Alliance, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba 305-8577, Japan; Center for Medical Genomics, National Cancer Center Research Institute, 5-1-1 Tsukiji Chuo-ku, Tokyo 104-0045, Japan; Department of Molecular Biology and Applied Physiology, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan

* To whom correspondence should be addressed. Email: masi{at}tara.tsukuba.ac.jp.


   Abstract

NF-E2 related factor 2 (Nrf2) regulates antioxidant responsive element (ARE)-mediated induction of cytoprotective genes in response to oxidative stress. The purpose of this study is to determine the role of BRG1, a catalytic subunit of SWI2/SNF2-like chromatin remodeling complexes, in Nrf2-mediated gene expression. SiRNA knockdown of BRG1 in SW480 cells selectively decreased inducible expression of heme oxygenase-1 (HO-1) gene after diethylmaleate (DEM) treatment, but did not affect other Nrf2-target genes, such as NAD(P)H:quinone oxidoreductase 1 (NQO1). Chromatin immunoprecipitation analysis revealed that Nrf2 recruits BRG1 to both HO-1 and NQO1 regulatory regions. However, BRG1 knockdown selectively decreased the recruitment of RNA polymerase II to the HO-1, but not to the NQO1 promoter. HO-1, but not other Nrf2-regulated genes, harbors a sequence of TG repeats capable of forming Z-DNA with the BRG1 assistance. Similarly, substitution of the TG repeats with an alternative Z-DNA-forming sequence led to BRG1-mediated activation of HO-1. These results thus demonstrate that BRG1, through the facilitation of Z-DNA formation and subsequent recruitment of RNA polymerase II, is critical in Nrf2-mediated inducible expression of HO-1.




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