Direct binding of DNA by tumor suppressor menin.
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 tumorigenesis. 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.
Abramson Family Cancer Research Institute, Department of Cancer Biology and Signal Transduction Program, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6160, USA.
Ping
P
La
Albert C
AC
Silva
Zhaoyuan
Z
Hou
Haoren
H
Wang
Robert W
RW
Schnepp
Nieng
N
Yan
Yigong
Y
Shi
Xianxin
X
Hua
D000818:Animals; D017304:Annexin A5 / Q000494:pharmacology; D017209:Apoptosis; D015153:Blotting, Western; D002455:Cell Division; D002460:Cell Line; D049109:Cell Proliferation; D002469:Cell Separation; D002478:Cells, Cultured; D004247:DNA / Q000737:chemistry*; D004268:DNA-Binding Proteins / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D016195:G2 Phase; D006801:Humans; D051379:Mice; D008856:Microscopy, Fluorescence; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D009690:Nucleic Acid Conformation; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism*
D017304:Annexin A5; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; C105373:MEN1 protein, human; D011518:Proto-Oncogene Proteins; D004247:DNA