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J. Biol. Chem., Vol. 279, Issue 47, 49045-49054, November 19, 2004

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Direct Binding of DNA by Tumor Suppressor Menin^*

Ping La, Albert C. Silva, Zhaoyuan Hou, Haoren Wang, Robert W. Schnepp, Nieng Yan, Yigong Shi, and Xianxin Hua¶

From the Abramson Family Cancer Research Institute, Department of Cancer Biology and Signal Transduction Program, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6160 and the Department of Molecular Biology, Princeton University, Lewis Thomas Laboratory, Princeton, New Jersey 08544

Menin is a tumor suppressor that is mutated in patients with multiple endocrine neoplasia type I (MEN1), an inherited tumor-prone syndrome. Because there is no obvious conserved structural domain in menin that suggests a biochemical function, little is known as to how menin suppresses tumorigenisis. Although menin interacts with a variety of nuclear proteins including transcription factors, it is unknown whether menin itself can directly bind DNA. Here we show that menin directly binds to double-stranded DNA. It also binds a variety of DNA structures, including Y-structures, branched structures, and 4-way junction structures. The COOH terminus of menin mediates binding to DNA, but MEN1 disease-derived mutations in the COOH terminus abolish the ability of menin to bind DNA. Importantly, these MEN1 disease-related menin mutants also fail to repress cell proliferation as well as cell cycle progression at the G₂/M phase. Furthermore, detailed mutagenesis studies indicate that positively charged residues in two nuclear localization signals mediate direct DNA binding as well as repression of cell proliferation. Collectively, these results demonstrate, for the first time, a novel biochemical activity of menin, binding to DNA, and link its DNA binding to the regulation of cell proliferation.

Received for publication, August 16, 2004

^* This work was supported by National Institutes of Health Grant R01 CA113962 (to X. H.), Research Grant RSG-03-055-01-LIB from American Cancer Society (to X. H.), and a scholar award from the Rita Alan Foundation (to X. H.). 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.

^¶ To whom correspondence should be addressed. Tel.: 215-746-5565; Fax: 215-746-5525; E-mail: huax{at}mail.med.upenn.edu.

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