Direct binding of DNA by tumor suppressor menin

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

Research output: Contribution to journalArticle

62 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)49045-49054
Number of pages10
JournalJournal of Biological Chemistry
Volume279
Issue number47
DOIs
StatePublished - Nov 19 2004

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    La, P., Silva, A. C., Hou, Z., Wang, H., Schnepp, R. W., Yan, N., Shi, Y., & Hua, X. (2004). Direct binding of DNA by tumor suppressor menin. Journal of Biological Chemistry, 279(47), 49045-49054. https://doi.org/10.1074/jbc.M409358200