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Molecular and Cellular Biology, July 2005, p. 5552-5566, Vol. 25, No. 13
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.13.5552-5566.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Histone Acetyltransferase Activity of p300 Is Required for Transcriptional Repression by the Promyelocytic Leukemia Zinc Finger Protein

Fabien Guidez,^1, Louise Howell,¹ Mark Isalan,² Marek Cebrat,^3,4 Rhoda M. Alani,⁵ Sarah Ivins,¹ Itsaso Hormaeche,⁶ Melanie J. McConnell,⁶ Sarah Pierce,¹ Philip A. Cole,³ Jonathan Licht,⁶ and Arthur Zelent^1*

Section of Haemato-Oncology, Institute of Cancer Research, Chester Beatty Laboratories, 237 Fulham Road, London SW3 6JB, United Kingdom,¹ EMBL Heidelberg, Meyerhofstrasse 1, D-69117 Heidelberg, Germany,² Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205,³ Faculty of Chemistry, University of Wroclaw, 50-383 Wroclaw, Poland,⁴ Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205,⁵ Division of Hematology/Oncology, Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029⁶

Received 18 August 2004/ Returned for modification 10 October 2004/ Accepted 31 March 2005

Histone acetyltransferase (HAT) activities of proteins such as p300, CBP, and P/CAF play important roles in activation of gene expression. We now show that the HAT activity of p300 can also be required for down-regulation of transcription by a DNA binding repressor protein. Promyelocytic leukemia zinc finger (PLZF), originally identified as a fusion with retinoic acid receptor alpha in rare cases of all-trans-retinoic acid-resistant acute promyelocytic leukemia, is a transcriptional repressor that recruits histone deacetylase-containing corepressor complexes to specific DNA binding sites. PLZF associates with p300 in vivo, and its ability to repress transcription is specifically dependent on HAT activity of p300 and acetylation of lysines in its C-terminal C₂-H₂ zinc finger motif. An acetylation site mutant of PLZF does not repress transcription and is functionally deficient in a colony suppression assay despite retaining its abilities to interact with corepressor/histone deacetylase complexes. This is due to the fact that acetylation of PLZF activates its ability to bind specific DNA sequences both in vitro and in vivo. Taken together, our results indicate that a histone deacetylase-dependent transcriptional repressor can be positively regulated through acetylation and point to an unexpected role of a coactivator protein in transcriptional repression.

Present address: Department of Medical and Molecular Genetics, Guy's, King's and St. Thomas' School of Medicine, 8th Floor, Guy's Tower, London, United Kingdom.

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