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Molecular and Cellular Biology, April 2003, p. 2633-2644, Vol. 23, No. 8
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.8.2633-2644.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

The CBP Bromodomain and Nucleosome Targeting Are Required for Zta-Directed Nucleosome Acetylation and Transcription Activation

Zhong Deng,1 Chi-Ju Chen,1 Michaela Chamberlin,1 Fang Lu,1 Gerd A. Blobel,2 David Speicher,1 Lisa Ann Cirillo,3 Kenneth S. Zaret,3 and Paul M. Lieberman1*

The Wistar Institute,1 Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104,2 Fox Chase Cancer Center, Philadelphia, Pennsylvania 191113

Received 19 November 2002/ Accepted 13 January 2003

The Epstein-Barr virus (EBV)-encoded lytic activator Zta is a bZIP protein that can stimulate nucleosomal histone acetyltransferase (HAT) activity of the CREB binding protein (CBP) in vitro. We now show that deletion of the CBP bromo- and C/H3 domains eliminates stimulation of nucleosomal HAT activity in vitro and transcriptional coactivation by Zta in transfected cells. In contrast, acetylation of free histones was not affected by the addition of Zta or by deletions in the bromo or C/H3 domain of CBP. Zta stimulated acetylation of oligonucleosomes assembled on supercoiled DNA and dinucleosomes assembled on linear DNA, but Zta-stimulated acetylation was significantly reduced for mononucleosomes. Western blotting and amino-terminal protein sequencing indicated that all lysine residues in the H3 and H4 amino-terminal tails were acetylated by CBP and enhanced by the addition of Zta. Histone acetylation was also dependent upon the Zta basic DNA binding domain, which could not be substituted with the homologous basic region of c-Fos, indicating specificity in the bZIP domain nucleosome binding function. Finally, we show that Zta and CBP colocalize to viral immediate-early promoters in vivo and that overexpression of Zta leads to a robust increase in H3 and H4 acetylation at various regions of the EBV genome in vivo. Furthermore, deletion of the CBP bromodomain reduced stable CBP-Zta complex formation and histone acetylation at Zta-responsive viral promoters in vivo. These results suggest that activator- and bromodomain-dependent targeting to oligonucleosomal chromatin is required for stable promoter-bound complex formation and transcription activity.

* Corresponding author. Mailing address: The Wistar Institute, Philadelphia, PA 19104. Phone: (215) 898-9491. Fax: (215) 898-0663. E-mail: lieberman{at}wistar.upenn.edu.

Molecular and Cellular Biology, April 2003, p. 2633-2644, Vol. 23, No. 8
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.8.2633-2644.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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