1. Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, Pennsylvania, 19104, USA
2. Research Institute of Molecular Pathology (IMP), The Vienna Biocenter, Vienna, A-1030, Austria
3. These authors contributed equally to this work.

Correspondence to: Shelley L. Berger¹ Correspondence and requests for materials should be addressed to S.L.B. (Email: berger@wistar.org).

Abstract

Specific sites of lysine methylation on histones correlate with either activation or repression of transcription^{1, 2, 3}. The tumour suppressor p53 (refs 4–7) is one of only a few non-histone proteins known to be regulated by lysine methylation⁸. 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.

MORE ARTICLES LIKE THIS

These links to content published by NPG are automatically generated.