Methylation of p53 by Set7/9 mediates p53 acetylation and activity in vivo.
The protein methyltransferase Set7/9 was recently shown to regulate p53 activity in cancer cells. However, the impact of Set7/9 on p53 function in vivo is unclear. To explore these issues, we created a null allele of Set7/9 in mice. Cells from Set7/9 mutant mice fail to methylate p53 K369, are unable to induce p53 downstream targets upon DNA damage, and are predisposed to oncogenic transformation. Importantly, we find that methylation of p53 by Set7/9 is required for the binding of the acetyltransferase Tip60 to p53 and for the subsequent acetylation of p53. We provide the first genetic evidence demonstrating that lysine methylation of p53 by Set7/9 is important for p53 activation in vivo and suggest a mechanistic link between methylation and acetylation of p53 through Tip60.
Kurash
Julia K
JK
Epigenetics, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
Lei
Hong
H
Shen
Qiong
Q
Marston
Wendy L
WL
Granda
Brian W
BW
Fan
Hong
H
Wall
Daniel
D
Li
En
E
Gaudet
François
F
D000107:Acetylation; D000123:Acetyltransferases / Q000378:metabolism; D000818:Animals; D002453:Cell Cycle / Q000502:physiology; D002460:Cell Line; D002461:Cell Line, Transformed; D002472:Cell Transformation, Viral; D004249:DNA Damage / Q000235:genetics; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000378:metabolism; D018628:Gene Dosage; D005982:Glutathione Transferase / Q000378:metabolism; D045325:HCT116 Cells; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007668:Kidney / Q000166:cytology; D008239:Lysine / Q000378:metabolism; D008745:Methylation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D011496:Protein Methyltransferases / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D016159:Tumor Suppressor Protein p53; D000076983:Histone Methyltransferases; D011496:Protein Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; C540312:SETD7 protein, human; C562044:Setd7 protein, mouse; D000123:Acetyltransferases; D005982:Glutathione Transferase; D008239:Lysine