title: Repression of p53 activity by Smyd2-mediated methylation.
abstract: 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.
authors.affiliation: Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Huang
authors.forename: Laura
authors.initials: L
authors.lastname: Perez-Burgos
authors.forename: Brandon J
authors.initials: BJ
authors.lastname: Placek
authors.forename: Roopsha
authors.initials: R
authors.lastname: Sengupta
authors.forename: Mario
authors.initials: M
authors.lastname: Richter
authors.forename: Jean A
authors.initials: JA
authors.lastname: Dorsey
authors.forename: Stefan
authors.initials: S
authors.lastname: Kubicek
authors.forename: Susanne
authors.initials: S
authors.lastname: Opravil
authors.forename: Thomas
authors.initials: T
authors.lastname: Jenuwein
authors.forename: Shelley L
authors.initials: SL
authors.lastname: Berger
mesh_terms: 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*
chemical_list: D016159:Tumor Suppressor Protein p53; D011495:Histone-Lysine N-Methyltransferase; C512569:SMYD2 protein, human; D008239:Lysine