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Repression of p53 activity by Smyd2-mediated methylation

Author

Listed:
  • Jing Huang

    (Gene Expression and Regulation Program, The Wistar Institute)

  • Laura Perez-Burgos

    (Research Institute of Molecular Pathology (IMP), The Vienna Biocenter)

  • Brandon J. Placek

    (Gene Expression and Regulation Program, The Wistar Institute)

  • Roopsha Sengupta

    (Research Institute of Molecular Pathology (IMP), The Vienna Biocenter)

  • Mario Richter

    (Research Institute of Molecular Pathology (IMP), The Vienna Biocenter)

  • Jean A. Dorsey

    (Gene Expression and Regulation Program, The Wistar Institute)

  • Stefan Kubicek

    (Research Institute of Molecular Pathology (IMP), The Vienna Biocenter)

  • Susanne Opravil

    (Research Institute of Molecular Pathology (IMP), The Vienna Biocenter)

  • Thomas Jenuwein

    (Research Institute of Molecular Pathology (IMP), The Vienna Biocenter)

  • Shelley L. Berger

    (Gene Expression and Regulation Program, The Wistar Institute)

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.

Suggested Citation

  • Jing Huang & Laura Perez-Burgos & Brandon J. Placek & Roopsha Sengupta & Mario Richter & Jean A. Dorsey & Stefan Kubicek & Susanne Opravil & Thomas Jenuwein & Shelley L. Berger, 2006. "Repression of p53 activity by Smyd2-mediated methylation," Nature, Nature, vol. 444(7119), pages 629-632, November.
    • Handle: RePEc:nat:nature:v:444:y:2006:i:7119:d:10.1038_nature05287
    DOI: 10.1038/nature05287
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    Cited by:

    1. Qifeng Bai & Yulin Shen & Xiaojun Yao & Fang Wang & Yuping Du & Qin Wang & Nengzhi Jin & Jun Hai & Tiejun Hu & Jinbo Yang, 2011. "Modeling a New Water Channel That Allows SET9 to Dimethylate p53," PLOS ONE, Public Library of Science, vol. 6(5), pages 1-9, May.

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