title: Regulation of p53 activity through lysine methylation.
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.
authors.affiliation: Howard Hughes Medical Institute, Division of Nucleic Acids Enzymology, Department of Biochemistry, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, USA.
authors.forename: Sergei
authors.initials: S
authors.lastname: Chuikov
authors.forename: Julia K
authors.initials: JK
authors.lastname: Kurash
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Wilson
authors.forename: Bing
authors.initials: B
authors.lastname: Xiao
authors.forename: Neil
authors.initials: N
authors.lastname: Justin
authors.forename: Gleb S
authors.initials: GS
authors.lastname: Ivanov
authors.forename: Kristine
authors.initials: K
authors.lastname: McKinney
authors.forename: Paul
authors.initials: P
authors.lastname: Tempst
authors.forename: Carol
authors.initials: C
authors.lastname: Prives
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Gamblin
authors.forename: Nickolai A
authors.initials: NA
authors.lastname: Barlev
authors.forename: Danny
authors.initials: D
authors.lastname: Reinberg
mesh_terms: D000595:Amino Acid Sequence; D017209:Apoptosis; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D005786:Gene Expression Regulation; D016158:Genes, p53 / Q000235:genetics; D011905:Genes, ras / Q000235:genetics; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000378:metabolism*; D008745:Methylation; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D011487:Protein Conformation; D011496:Protein Methyltransferases; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012435:S-Adenosylhomocysteine / Q000378:metabolism; D013379:Substrate Specificity; D013816:Thermodynamics; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D012435:S-Adenosylhomocysteine; D000076983:Histone Methyltransferases; D011496:Protein Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; C540312:SETD7 protein, human; D008239:Lysine