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J. Biol. Chem., Vol. 283, Issue 29, 20060-20068, July 18, 2008

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Histone Arg Modifications and p53 Regulate the Expression of OKL38, a Mediator of Apoptosis^*

Hongjie Yao, Pingxin Li, Bryan J. Venters, Suting Zheng, Paul R. Thompson, B. Franklin Pugh, and Yanming Wang¹

From the Center for Gene Regulation, Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, Pennsylvania 16802 and the Department of Chemistry and Biochemistry, University of South Carolina, Columbia, South Carolina 29208

Protein Arg methyltransferases function as coactivators of the tumor suppressor p53 to regulate gene expression. Peptidylarginine deiminase 4 (PAD4/PADI4) counteracts the functions of protein Arg methyltransferases in gene regulation by deimination and demethylimination. Here we show that the expression of a tumor suppressor gene, OKL38, is activated by the inhibition of PAD4 or the activation of p53 following DNA damage. Chromatin immunoprecipitation assays showed a dynamic change of p53 and PAD4 occupancy and histone Arg modifications at the OKL38 promoter during DNA damage, suggesting a direct role of PAD4 and p53 in the expression of OKL38. Furthermore, we found that OKL38 induces apoptosis through localization to mitochondria and induction of cytochrome c release. Together, our studies identify OKL38 as a novel p53 target gene that is regulated by PAD4 and plays a role in apoptosis.

Received for publication, April 17, 2008 , and in revised form, May 21, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant GM079357 (to P. R. T.). This work was also supported by a startup fund from Pennsylvania State University (to Y. W.) and a TSF seed grant award from Johnson & Johnson Inc. and Pennsylvania State University. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Experimental Procedures, additional references, and Figs. S1–S7.

¹ To whom correspondence should be addressed: 332 South Frear, University Park, PA 16802. E-mail: yuw12{at}psu.edu.

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