Open AccessUbiquitination of Lysine 867 of the Human SETDB1 Protein Upregulates Its Histone H3 Lysine 9 (H3K9) Methyltransferase Activity
Author(s) -
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
Publication year - 2016
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0165766
Subject(s) - histone methyltransferase , methyltransferase , histone h3 , lysine , histone , ubiquitin , biology , methylation , biochemistry , histone methylation , ezh2 , acetylation , microbiology and biotechnology , chemistry , gene expression , gene , dna methylation , amino acid
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.