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PLoS One. 2016 Oct 31;11(10):e0165766. doi: 10.1371/journal.pone.0165766. eCollection 2016.

Ubiquitination of Lysine 867 of the Human SETDB1 Protein Upregulates Its Histone H3 Lysine 9 (H3K9) Methyltransferase Activity.

Author information

1
Laboratory of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan.
2
Laboratory for System Biology and Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, Meguro, Tokyo, Japan.
3
Department of Applied Chemistry, Graduate School of Engineering, Osaka University, Suita, Osaka, Japan.
4
Department of Quantitative Biology and Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, Meguro, Tokyo, Japan.
5
Division of Metabolic Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, Meguro, Tokyo, Japan.

Abstract

Posttranslational modifications (PTMs) of proteins play a crucial role in regulating protein-protein 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.

PMID:
27798683
PMCID:
PMC5087952
DOI:
10.1371/journal.pone.0165766
[Indexed for MEDLINE]
Free PMC Article

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