Editors' ChoicePosttranslational Modifications

Stabilizing p53 with Methylation

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Science's STKE  23 Nov 2004:
Vol. 2004, Issue 260, pp. tw422
DOI: 10.1126/stke.2602004tw422

The activity of the tumor suppressor p53 is regulated through posttranslational modifications, including phosphorylation, acetylation, ubiquitination, and sumoylation. Chuikov et al. observed that the lysine-specific methyltransferase Set9 methylated p53 (but not various other proteins), whereas several other protein methyltransferases did not. Set9 selectively methylated a single lysine, K372, in the p53 C-terminus regulatory domain, a region that is also subject to phosphorylation and acetylation. The authors performed Western-blot analysis with an antibody that specifically recognized p53 methylated at K372 to show that wild-type Set9 methylated p53 when overexpressed in 293F cells, whereas catalytically inactive Set9 did not. The 293F or U2OS cells treated with adriamycin to elicit DNA damage showed increased p53 methylation with no change in Set9 content, whereas introduction of Set9 siRNA into U2OS cells reduced p53 methylation in response to adriamycin. Methylated p53 was localized to the nucleus, and Set9 overexpression enhanced transcription of the p53 target p21 and increased p53-dependent apoptosis, even in the absence of DNA damage, whereas p21 transcription in response to DNA damage was blocked by overexpression of the catalytically inactive Set9 mutant or by Set9 siRNA. The amount of intracellular p53 was also reduced by the Set9 mutant and by Set9 siRNA, and analysis of 35S-labeled p53 at various times after exposure to radiolabeled methionine indicated that Set9 stabilized chromatin-bound p53, an effect that depended on K372 (as did Set9 stimulation of p21 transcription). Thus, methylation appears to represent another posttranslational modification whereby the activity of p53 can be modulated.

S. Chuikov, J. K. Kurash, J. R. Wilson, B. Xiao, N. Justin, G. S. Ivanov, K. McKinney, P. Tempst, C. Prives, S. J. Gamblin, N. K. Barlev, D. Reinberg, Regulation of p53 activity through lysine methylation. Nature 432, 353-360 (2004). [Online Journal]

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