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Regulation of p53 activity through lysine methylation.

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.

Pubmed ID: 15525938

Authors

  • Chuikov S
  • Kurash JK
  • Wilson JR
  • Xiao B
  • Justin N
  • Ivanov GS
  • McKinney K
  • Tempst P
  • Prives C
  • Gamblin SJ
  • Barlev NA
  • Reinberg D

Journal

Nature

Publication Data

November 18, 2004

Associated Grants

None

Mesh Terms

  • Amino Acid Sequence
  • Apoptosis
  • Cell Line
  • Cell Nucleus
  • Gene Expression Regulation
  • Genes, p53
  • Genes, ras
  • Histone-Lysine N-Methyltransferase
  • Humans
  • Lysine
  • Methylation
  • Models, Molecular
  • Molecular Sequence Data
  • Promoter Regions, Genetic
  • Protein Binding
  • Protein Conformation
  • Protein Methyltransferases
  • RNA, Messenger
  • S-Adenosylhomocysteine
  • Substrate Specificity
  • Thermodynamics
  • Tumor Suppressor Protein p53