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Mol Cell Biol, March 1998, p. 1349-1358, Vol. 18, No. 3
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Repression of GCN5 Histone Acetyltransferase Activity via Bromodomain-Mediated Binding and Phosphorylation by the Ku-DNA-Dependent Protein Kinase Complex

Nickolai A. Barlev,1 Vladimir Poltoratsky,2 Tom Owen-Hughes,3 Carol Ying,1 Lin Liu,1 Jerry L. Workman,3 and Shelley L. Berger1,*

The Wistar Institute, Philadelphia, Pennsylvania 191041; St. John University, New York, New York 114392; and Pennsylvania State University, State College, Pennsylvania 168023

Received 9 October 1997/Returned for modification 12 November 1997/Accepted 15 December 1997

GCN5, a putative transcriptional adapter in humans and yeast, possesses histone acetyltransferase (HAT) activity which has been linked to GCN5's role in transcriptional activation in yeast. In this report, we demonstrate a functional interaction between human GCN5 (hGCN5) and the DNA-dependent protein kinase (DNA-PK) holoenzyme. Yeast two-hybrid screening detected an interaction between the bromodomain of hGCN5 and the p70 subunit of the human Ku heterodimer (p70-p80), which is the DNA-binding component of DNA-PK. Interaction between intact hGCN5 and Ku70 was shown biochemically using recombinant proteins and by coimmunoprecipitation of endogenous proteins following chromatography of HeLa nuclear extracts. We demonstrate that the catalytic subunit of DNA-PK phosphorylates hGCN5 both in vivo and in vitro and, moreover, that the phosphorylation inhibits the HAT activity of hGCN5. These findings suggest a possible regulatory mechanism of HAT activity.

* Corresponding author. Mailing address: The Wistar Institute, 3601 Spruce St., Room 358, Philadelphia, PA 19104. Phone: (215) 898-3922. Fax: (215) 898-0663. E-mail: berger{at}wista.wistar.upenn.edu.




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