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J. Biol. Chem., Vol. 282, Issue 13, 9312-9322, March 30, 2007

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Phosphorylation of Thyroid Hormone Receptor-associated Nuclear Receptor Corepressor Holocomplex by the DNA-dependent Protein Kinase Enhances Its Histone Deacetylase Activity^*

M. Jeyakumar, Xue-feng Liu, Hediye Erdjument-Bromage, Paul Tempst, and Milan K. Bagchi¹

From the Department of Molecular and Integrative Physiology, University of Illinois, Urbana, Illinois 61801 and Memorial Sloan-Kettering Cancer Center, New York, New York 10021

It is well documented that unliganded thyroid hormone receptor (TR) functions as a transcriptional repressor of specific cellular target genes by acting in concert with a corepressor complex harboring histone deacetylase (HDAC) activity. To fully explore the cofactors that interact with the transcriptionally repressive form of TR, we biochemically isolated a multiprotein complex that assembles on a TR·retinoid X receptor (RXR) heterodimer in HeLa nuclear extracts and identified its polypeptide components by mass spectrometry. A subset of TR·RXR-associated polypeptides included NCoR, SMRT, TBL1, and HDAC3, which represent the core components of a previously described NCoR/SMRT corepressor complex. We also identified several polypeptides that constitute a DNA-dependent protein kinase (DNA-PK) enzyme complex, a regulator of DNA repair, recombination, and transcription. These polypeptides included the catalytic subunit DNA-PKcs, the regulatory subunits Ku70 and Ku86, and the poly(ADP-ribose) polymerase 1. Density gradient fractionation and immunoprecipitation analyses provided evidence for the existence of a high molecular weight TR·RXR·corepressor holocomplex containing both NCoR/SMRT and DNA-PK complexes. Chromatin immunoprecipitation studies confirmed that unliganded TR·RXR recruits both complexes to the triiodothyronine-responsive region of growth hormone gene in vivo. Interestingly, DNA-PKcs, a member of the phosphatidylinositol 3-kinase family, was found to phosphorylate HDAC3 when the purified TR·RXR·corepressor holocomplex was incubated with ATP. This phosphorylation was accompanied by a significant enhancement of the HDAC activity of this complex. Collectively, our results indicated that DNA-PK promotes the establishment of a repressive chromatin at a TR target promoter by enhancing the HDAC activity of the receptor-bound NCoR/SMRT corepressor complex.

Received for publication, September 22, 2006 , and in revised form, January 22, 2007.

^* This work was supported by National Institutes of Health Grant DK50257 (to M. K. B.) and NCI Cancer Center Support Grant P30 CA08748 (to P. T.). 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.

¹ To whom correspondence should be addressed: Dept. of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, 534 Burrill Hall, 407 S. Goodwin Ave., Urbana, IL 61801. Tel.: 217-244-5054; Fax: 217-333-1133; E-mail: mbagchi{at}life.uiuc.edu.

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