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.
Chuikov
Sergei
S
Howard Hughes Medical Institute, Division of Nucleic Acids Enzymology, Department of Biochemistry, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, USA.
Kurash
Julia K
JK
Wilson
Jonathan R
JR
Xiao
Bing
B
Justin
Neil
N
Ivanov
Gleb S
GS
McKinney
Kristine
K
Tempst
Paul
P
Prives
Carol
C
Gamblin
Steven J
SJ
Barlev
Nickolai A
NA
Reinberg
Danny
D
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*
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