Research for an mRNA modication specific to vertebrates

• Project/Area Number: 18K19141
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 37:Biomolecular chemistry and related fields
• Research Institution: The University of Tokyo
• Principal Investigator: Suzuki Takeo 東京大学, 大学院工学系研究科(工学部), 講師 (90533125)
• Project Period (FY): 2018-06-29 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000); Fiscal Year 2019: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000); Fiscal Year 2018: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000)
• Keywords: mRNA / メチル化 / 脊椎動物 / 修飾 / RNA修飾 / 生合成 / 遺伝子発現

Outline of Final Research Achievements

We aimed to elucidate the function of the 5’-terminal N6-methyladenosine (1st-m6A) modification which is found only in vertebrates at the 5’-terminus of mRNA. We successfully identified the gene for the methyltransferase (MTase) for 1st-m6A, confirmed enzymatic methylation activity of the gene product in vitro and determined structural features of mRNA which can accept a N6-methyl group to the 1st-adenosine. Crystal structures of the MTase reveled amino acid residues which are essential to the MTase activity and recognition of substrate mRNA. Knocking out of the MTase gene in cultured cells showed the sensitivity to the oxidative stress. Furthermore, deep-sequencing analyses revealed that 1st-m6A modification contributes to enhance translation efficiency of mRNAs harboring 1st-m6A.

Academic Significance and Societal Importance of the Research Achievements

1970年代における始端m6Aの発見以降、生合成や機能が不明なまま約40年が経過していたが、今回、始端m6A修飾の生合成機構や機能的意義の解明にはじめて成功した。始端m6A修飾は我々ヒトを含む脊椎動物で主に見いだされる、生物種分布が特徴的な修飾である。脊椎動物の生物種としての特徴を深く理解する上でも、始端m6A形成メカニズムの解明は一定の意義があると言えるだろう。

Research Products

• [Journal Article] Cap-specific terminal N6-methylation of RNA by an RNA polymerase II?associated methyltransferase (2018)
  • Author(s): Akichika Shinichiro、Hirano Seiichi、Shichino Yuichi、Suzuki Takeo、Nishimasu Hiroshi、Ishitani Ryuichiro、Sugita Ai、Hirose Yutaka、Iwasaki Shintaro、Nureki Osamu、Suzuki Tsutomu
  • Journal Title: Science Volume: 363 Issue: 363 Pages: 1-7
  • DOI: 10.1126/science.aav0080
  • Peer Reviewed / Open Access
• [Journal Article] ヒドロキシル化 (2018)
  • Author(s): 鈴木, 健夫、 鈴木, 勉
  • Journal Title: 生体の科学 Volume: 69 Pages: 398-399
• [Presentation] Cap-specific terminal N6-methylation of RNA by an RNA polymerase II-associated methyltransferase (2019)
  • Author(s): Akichika, S., Hirano, S., Shichino, Y., Suzuki, T., Nishimasu, H., Ishitani, R., Sugita, A., Hirose, Y., Iwasaki, S., Nureki, O., Suzuki, T.
  • Organizer: 21st RNA meeting
• [Presentation] Cap-specific terminal N6-methylation of RNA by an RNA polymerase II-associated methyltransferase (2019)
  • Author(s): Akichika, S., Hirano, S., Shichino, Y., Suzuki, T., Nishimasu, H., Ishitani, R., Sugita, A., Hirose, Y., Iwasaki, S., Nureki, O., Suzuki, T.
  • Organizer: 20th Takeda Science Foundation Symposium on Bioscience, RNA Neobiology
  • Int'l Joint Research
• [Presentation] Identification and characterization of tRNA queuosine-glycosyltransferase in mammal (2019)
  • Author(s): Ma, D., Zhao, X., Suzuki, T., Suzuki, T.
  • Organizer: 20th Takeda Science Foundation Symposium on Bioscience, RNA Neobiology
  • Int'l Joint Research
• [Presentation] ミトコンドリアにおける暗号解読の担い手：tRNA修飾 (2018)
  • Author(s): 鈴木, 健夫
  • Organizer: 第18回日本ミトコンドリア学会年会
  • Invited
• [Presentation] ヒト疾患に関わるtRNAタウリン修飾の生合成と代謝制御 (2018)
  • Author(s): Suzuki, T., Asano, K., Saito, A., Wei, F. Y., Tomizawa, K., Sakaguchi, Y., Suzuki, T.
  • Organizer: 20th RNA meeting
• [Remarks] 東京大学大学院工学系研究科 プレスリリース
  • URL: https://www.t.u-tokyo.ac.jp/soe/press/setnws_201811270918295542170205.html