Abstract
p53 is a tumour suppressor that regulates the cellular response to genotoxic stresses. p53 is a short-lived protein and its activity is regulated mostly by stabilization via different post-translational modifications. Here we report a novel mechanism of p53 regulation through lysine methylation by Set9 methyltransferase. Set9 specifically methylates p53 at one residue within the carboxyl-terminus regulatory region. Methylated p53 is restricted to the nucleus and the modification positively affects its stability. Set9 regulates the expression of p53 target genes in a manner dependent on the p53-methylation site. The crystal structure of a ternary complex of Set9 with a p53 peptide and the cofactor product S-adenosyl-l-homocysteine (AdoHcy) provides the molecular basis for recognition of p53 by this lysine methyltransferase.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Apoptosis
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Cell Line
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Cell Nucleus / metabolism
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Gene Expression Regulation
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Genes, p53 / genetics
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Genes, ras / genetics
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Histone Methyltransferases
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Histone-Lysine N-Methyltransferase / chemistry
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Histone-Lysine N-Methyltransferase / genetics
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Histone-Lysine N-Methyltransferase / metabolism*
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Humans
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Lysine / metabolism*
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Methylation
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Models, Molecular
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Molecular Sequence Data
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Promoter Regions, Genetic / genetics
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Protein Binding
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Protein Conformation
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Protein Methyltransferases
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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S-Adenosylhomocysteine / metabolism
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Substrate Specificity
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Thermodynamics
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Tumor Suppressor Protein p53 / chemistry*
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Tumor Suppressor Protein p53 / metabolism*
Substances
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RNA, Messenger
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Tumor Suppressor Protein p53
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S-Adenosylhomocysteine
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Histone Methyltransferases
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Protein Methyltransferases
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Histone-Lysine N-Methyltransferase
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SETD7 protein, human
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Lysine