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J. Biol. Chem., Vol. 282, Issue 50, 36603-36613, December 14, 2007

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 282/50/36603    most recent M705812200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Holbert, M. A. Articles by Marmorstein, R. Search for Related Content PubMed PubMed Citation Articles by Holbert, M. A. Articles by Marmorstein, R. Social Bookmarking                      What's this?

The Human Monocytic Leukemia Zinc Finger Histone Acetyltransferase Domain Contains DNA-binding Activity Implicated in Chromatin Targeting^*

Marc A. Holbert, Timothy Sikorski, Juliana Carten, Danielle Snowflack, Santosh Hodawadekar, and Ronen Marmorstein¹

From the The Wistar Institute and Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104-0381

The human monocytic leukemia zinc finger (MOZ) protein is an essential transcriptional coactivator and histone acetyltransferase (HAT) that plays a primary role in the differentiation of erythroid and myeloid cells and is required to maintain hematopoietic stem cells. Chromosomal translocations involving the HAT-encoded region are also associated with acute myeloid leukemia. Here we present the x-ray crystal structure of the MOZ HAT domain and related biochemical studies. We find that the HAT domain contains a central region that is structurally and functionally conserved with the yeast MYST HAT protein Esa1, but contains more divergent N- and C-terminal regions harboring a TFIIIA-type zinc finger and helix-turn-helix DNA-binding motifs. Solution DNA-binding and acetyltransferase activity assays, in concert with mutagenesis, confirm that the MOZ HAT domain binds strongly to DNA through the zinc finger and helix-turn-helix motifs and that DNA binding and catalysis are not mutually exclusive. Consistent with the DNA-binding properties of MOZ, we also show that MOZ is able to acetylate nucleosomes and free histones equally well, whereas other HATs prefer free histones. Our results reveal, for the first time, that enzymatic and DNA-targeting activities can be contained within the same chromatin regulatory domain.

Received for publication, July 16, 2007 , and in revised form, September 20, 2007.

The atomic coordinates and structure factors (code 2RC4) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported by National Institutes of Health Grant GM60293 (to R. M.) and a grant from the Commonwealth Universal Research Enhancement Program, Pennsylvania Department of Health awarded to the Wistar Institute. 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 Fig. S1 and an additional reference.

¹ To whom correspondence should be addressed: The Wistar Institute, 3601 Spruce St., Philadelphia, PA 19104-4268. Tel.: 215-898-5006; Fax: 215-898-0381; E-mail: marmor{at}wistar.org.

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