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J. Biol. Chem., Vol. 281, Issue 22, 15129-15137, June 2, 2006

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NAB2 Represses Transcription by Interacting with the CHD4 Subunit of the Nucleosome Remodeling and Deacetylase (NuRD) Complex^*

Rajini Srinivasan¹, Gennifer M. Mager¹, Rebecca M. Ward, Joshua Mayer^¶, and John Svaren^¶2

From the Department of Comparative Biosciences, the Molecular and Cellular Pharmacology Training Program, and the ^¶Cellular and Molecular Biology Training Program, University of Wisconsin, Madison, Wisconsin 53706

Early growth response (EGR) transactivators act as critical regulators of several physiological processes, including peripheral nerve myelination and progression of prostate cancer. The NAB1 and NAB2 (NGFI-A/EGR1-binding protein) transcriptional corepressors directly interact with three EGR family members (Egr1/NGFI-A/zif268, Egr2/Krox20, and Egr3) and repress activation of their target promoters. To understand the molecular mechanisms underlying NAB repression, we found that EGR activity is modulated by at least two repression domains within NAB2, one of which uniquely requires interaction with the CHD4 (chromodomain helicase DNA-binding protein 4) subunit of the NuRD (nucleosome remodeling and deacetylase) chromatin remodeling complex. Both NAB proteins can bind either CHD3 or CHD4, indicating that the interaction is conserved among these two protein families. Furthermore, we show that repression of the endogenous Rad gene by NAB2 involves interaction with CHD4 and demonstrate colocalization of NAB2 and CHD4 on the Rad promoter in myelinating Schwann cells. Finally, we show that interaction with CHD4 is regulated by alternative splicing of the NAB2 mRNA.

Received for publication, January 25, 2006

^* This work was supported by Grant HD41590 from the National Institutes of Health, Grant W81XWH-06-1-0167 from the Dept. of Defense Prostate Cancer Research Program, and Core Grant P30 HD03352 to the Waisman Center from the NICHD, National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

This work is dedicated with gratitude to the memory of Wolfram Hörz (1944–2005).

¹ These authors contributed equally to this work.

² To whom correspondence should be addressed: 2015 Linden Dr., School of Veterinary Medicine, Madison, WI 53706. Tel.: 608-263-4246; Fax: 608-263-3926; E-mail: jpsvaren{at}wisc.edu.

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