Ubiquitination of lysine 867 of the human SETDB1 protein upregulates its histone H3 lysine 9 (H3K9) methyltransferase activity

Kenji Ishimoto, Natsuko Kawamata, Yoshie Uchihara, Moeka Okubo, Reiko Fujimoto, Eiko Gotoh, Keisuke Kakinouchi, Eiichi Mizohata, Nobumasa Hino, Yoshiaki Okada, Yasuhiro Mochizuki, Toshiya Tanaka, Takao Hamakubo, Juro Sakai, Tatsuhiko Kodama, Tsuyoshi Inoue, Keisuke Tachibana, Takefumi Doi

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6 Citations (Scopus)

Abstract

Posttranslational modifications (PTMs) of proteins play a crucial role in regulating proteinprotein interactions, enzyme activity, subcellular localization, and stability of the protein. SET domain, bifurcated 1 (SETDB1) is a histone methyltransferase that regulates the methylation of histone H3 on lysine 9 (H3K9), gene silencing, and transcriptional repression. The C-terminal region of SETDB1 is a key site for PTMs, and is essential for its enzyme activity in mammalian and insect cells. In this study, we aimed to evaluate more precisely the effect of PTMs on the H3K9 methyltransferase activity of SETDB1. Using mass spectrometry analysis, we show that the C-terminal region of human SETDB1 purified from insect cells is ubiquitinated. We also demonstrate that the ubiquitination of lysine 867 of the human SETDB1 is necessary for full H3K9 methyltransferase activity in mammalian cells. Finally, we show that SETDB1 ubiquitination regulates the expression of its target gene, serpin peptidase inhibitor, clade E, member 1 (SERPINE1) by methylating H3K9. These results suggest that the ubiquitination of SETDB1 at lysine 867 controls the expression of its target gene by activating its H3K9 methyltransferase activity.

Original languageEnglish
Article numbere0165766
JournalPloS one
Volume11
Issue number10
DOIs
Publication statusPublished - 2016 Oct

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Ishimoto, K., Kawamata, N., Uchihara, Y., Okubo, M., Fujimoto, R., Gotoh, E., Kakinouchi, K., Mizohata, E., Hino, N., Okada, Y., Mochizuki, Y., Tanaka, T., Hamakubo, T., Sakai, J., Kodama, T., Inoue, T., Tachibana, K., & Doi, T. (2016). Ubiquitination of lysine 867 of the human SETDB1 protein upregulates its histone H3 lysine 9 (H3K9) methyltransferase activity. PloS one, 11(10), [e0165766]. https://doi.org/10.1371/journal.pone.0165766