Analysis of molecular mechanism regulating enzyme function of histone methylation enzyme SETDB1

• Project/Area Number: 15H04644
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Biological pharmacy
• Research Institution: Osaka University
• Principal Investigator: DOI Takefumi 大阪大学, 薬学研究科, 教授 (00211409)
• Co-Investigator(Kenkyū-buntansha): 井上 豪 大阪大学, 工学研究科, 教授 (20263204) ; 橘 敬祐 大阪大学, 薬学研究科(研究院), 招へい教員 (30432446)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥16,770,000 (Direct Cost: ¥12,900,000、Indirect Cost: ¥3,870,000); Fiscal Year 2017: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2016: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2015: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000)
• Keywords: ヒストンメチル化 / 翻訳後修飾 / ユビキチン化 / ヒストン修飾 / メチル化 / SETDB1 / MCAF1 / 細胞内局在

Outline of Final Research Achievements

Molecular mechanisms that control the enzymatic function of SETDB1, an enzyme that specifically methylates histone H3K9, were analyzed by a multiple approach. (1) We demonstrated that mono-ubiquitination modification of SETDB1 regulates gene expression via H3K9me3 activity. In addition, TRIM28, a chromatin regulator, was identified as a factor related to its regulatory mechanism. (2) SETDB1 in the nucleus showed stable expression by proteasome inhibitor and nuclear export inhibitor, and ligase X was found as a candidate factor related to it. (3) In order to conduct X-ray crystal structure analysis of SETDB1-MCAF1, we performed protein purification and its crystallization. The novel finding of SETDB1 clarified in this research leads to the development of new cancer therapeutic drug targeting SETDB1.

Research Products

• [Journal Article] Ubiquitination of Lysine 867 of the Human SETDB1 Protein Upregulates Its Histone H3 Lysine 9 (H3K9) Methyltransferase Activity. (2016)
  • Author(s): 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
  • Journal Title: PLoS One Volume: 11 Issue: 10 Pages: e0165766-e0165766
  • DOI: 10.1371/journal.pone.0165766
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Analysis of the subcellular localization of the human histone methyltransferase SETDB1 (2015)
  • Author(s): Tachibana K, Gotoh E, Kawamata N, Ishimoto K, Uchihara Y, Iwanari H, Sugiyama A, Kawamura T, Mochizuki Y, Tanaka T, Sakai J, Hamakubo T, Kodama T, Doi T.
  • Journal Title: Biochem Biophys Res Commun Volume: 465 Issue: 4 Pages: 725-731
  • DOI: 10.1016/j.bbrc.2015.08.065
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Remarks] 大阪大学大学院薬学研究科生命情報解析学分野ホームページ
  • URL: https://seimeijohokaiseki.wixsite.com/tanpaku/publication
• [Remarks] 大阪大学薬学研究科生命情報解析学分野ホームページ
  • URL: http://www.osaka-u.ac.jp/homepage/b018/
• [Remarks] 大阪大学薬学研究科生命情報解析学分野ホームページ
  • URL: http://www.phs.osaka-u.ac.jp/homepage/b018/