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Repression of p53 activity by Smyd2-mediated methylation

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Abstract

Specific sites of lysine methylation on histones correlate with either activation or repression of transcription1,2,3. 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.

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Figure 1: Smyd2 methylates p53 at K370 in vitro.
Figure 2: Smyd2 methylates p53 at K370 in vivo.
Figure 3: Smyd2 represses the function of p53.
Figure 4: Cross-talk between p53K370me1 and p53K372me1.

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Acknowledgements

We thank N. Barlev for the Set9 expression vector and D. Reinberg for the p53K372me1 antibody; T. Waibel for assistance in cloning Smyd2; S. Benchimol for the BJ and BJ-DNp53 cell lines; and members of the T.J. and S.L.B. laboratories for discussions. Research in the laboratory of T.J. is supported by the IMP through Boehringer Ingelheim and by grants from the European Union and the Austrian GEN-AU initiative, which is financed by the Austrian Ministry of Education, Science and Culture. Research support to S.L.B. was provided by a grant from the NIH. B.J.P. was supported by a Wistar Cancer Training Grant.

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  1. Jing Huang and Laura Perez-Burgos: These authors contributed equally to this work.

Authors and Affiliations

  1. Gene Expression and Regulation Program, The Wistar Institute, Pennsylvania, 19104, Philadelphia, USA

    Jing Huang, Brandon J. Placek, Jean A. Dorsey & Shelley L. Berger

  2. Research Institute of Molecular Pathology (IMP), The Vienna Biocenter, Vienna, A-1030, Austria

    Laura Perez-Burgos, Roopsha Sengupta, Mario Richter, Stefan Kubicek, Susanne Opravil & Thomas Jenuwein

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  1. Jing Huang
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  2. Laura Perez-Burgos
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  3. Brandon J. Placek
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  4. Roopsha Sengupta
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  6. Jean A. Dorsey
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  9. Thomas Jenuwein
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  10. Shelley L. Berger
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Correspondence to Shelley L. Berger.

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Huang, J., Perez-Burgos, L., Placek, B. et al. Repression of p53 activity by Smyd2-mediated methylation. Nature 444, 629–632 (2006). https://doi.org/10.1038/nature05287

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