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Molecular and Cellular Biology, August 2008, p. 4745-4758, Vol. 28, No. 15
0270-7306/08/$08.00+0     doi:10.1128/MCB.01747-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Regulation of p53 Target Gene Expression by Peptidylarginine Deiminase 4 ^,

Pingxin Li,¹ Hongjie Yao,¹ Zhiqiang Zhang,¹ Ming Li,¹ Yuan Luo,² Paul R. Thompson,² David S. Gilmour,¹ and Yanming Wang^1*

Center for Gene Regulation, Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, Pennsylvania 16802,¹ Department of Chemistry and Biochemistry, University of South Carolina, 631 Sumter Street, Columbia, South Carolina 29208²

Received 24 September 2007/ Returned for modification 27 November 2007/ Accepted 20 May 2008

Histone Arg methylation has been correlated with transcriptional activation of p53 target genes. However, whether this modification is reversed to repress the expression of p53 target genes is unclear. Here, we report that peptidylarginine deiminase 4, a histone citrullination enzyme, is involved in the repression of p53 target genes. Inhibition or depletion of PAD4 elevated the expression of a subset of p53 target genes, including p21/CIP1/WAF1, leading to cell cycle arrest and apoptosis. Moreover, the induction of p21, cell cycle arrest, and apoptosis by PAD4 depletion is p53 dependent. Protein-protein interaction studies showed an interaction between p53 and PAD4. Chromatin immunoprecipitation assays showed that PAD4 is recruited to the p21 promoter in a p53-dependent manner. RNA polymerase II (Pol II) activities and the association of PAD4 are dynamically regulated at the p21 promoter during UV irradiation. Paused RNA Pol II and high levels of PAD4 were detected before UV treatment. At early time points after UV treatment, an increase of histone Arg methylation and a decrease of citrullination were correlated with a transient activation of p21. At later times after UV irradiation, a loss of RNA Pol II and an increase of PAD4 were detected at the p21 promoter. The dynamics of RNA Pol II activities after UV treatment were further corroborated by permanganate footprinting. Together, these results suggest a role of PAD4 in the regulation of p53 target gene expression.

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* Corresponding author. Mailing address: Center for Gene Regulation, Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802. Phone: (814) 865-3775. Fax: (814) 865-7770. E-mail: yuw12{at}psu.edu

Published ahead of print on 27 May 2008.

Supplemental material for this article may be found at http://mcb.asm.org/.

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Molecular and Cellular Biology, August 2008, p. 4745-4758, Vol. 28, No. 15
0270-7306/08/$08.00+0     doi:10.1128/MCB.01747-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

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