Repression of p53 activity by Smyd2-mediated methylation.
Specific sites of lysine methylation on histones correlate with either activation or repression of transcription. The tumour suppressor p53 (refs 4-7) is one of only a few non-histone proteins known to be regulated by lysine methylation. Here we report a lysine methyltransferase, Smyd2, that methylates a previously unidentified site, Lys 370, in p53. This methylation site, in contrast to the known site Lys 372, is repressing to p53-mediated transcriptional regulation. Smyd2 helps to maintain low concentrations of promoter-associated p53. We show that reducing Smyd2 concentrations by short interfering RNA enhances p53-mediated apoptosis. We find that Set9-mediated methylation of Lys 372 inhibits Smyd2-mediated methylation of Lys 370, providing regulatory cross-talk between post-translational modifications. In addition, we show that the inhibitory effect of Lys 372 methylation on Lys 370 methylation is caused, in part, by blocking the interaction between p53 and Smyd2. Thus, similar to histones, p53 is subject to both activating and repressing lysine methylation. Our results also predict that Smyd2 may function as a putative oncogene by methylating p53 and repressing its tumour suppressive function.
Huang
Jing
J
Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
Perez-Burgos
Laura
L
Placek
Brandon J
BJ
Sengupta
Roopsha
R
Richter
Mario
M
Dorsey
Jean A
JA
Kubicek
Stefan
S
Opravil
Susanne
S
Jenuwein
Thomas
T
Berger
Shelley L
SL
D000818:Animals; D002460:Cell Line; D005786:Gene Expression Regulation; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000378:metabolism*; D008745:Methylation; D051379:Mice; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D016159:Tumor Suppressor Protein p53; D011495:Histone-Lysine N-Methyltransferase; C512569:SMYD2 protein, human; D008239:Lysine