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Analysis of post-translation termination event

Research Project

Project/Area Number 20H03438
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 48040:Medical biochemistry-related
Research InstitutionUniversity of the Ryukyus

Principal Investigator

YAMASHITA AKIO  琉球大学, 医学(系)研究科(研究院), 教授 (20405020)

Project Period (FY) 2020-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥17,680,000 (Direct Cost: ¥13,600,000、Indirect Cost: ¥4,080,000)
Fiscal Year 2022: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
Fiscal Year 2021: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000)
Fiscal Year 2020: ¥6,630,000 (Direct Cost: ¥5,100,000、Indirect Cost: ¥1,530,000)
KeywordsmRNA分解 / mRNA翻訳 / ナンセンス変異 / mRNA監視機構 / NMD / 新生ポリペプチド / がん抗原 / 新生鎖 / mRNA分解制御 / mRNA翻訳制御 / キナーゼ / シャペロン / ストレス応答
Outline of Research at the Start

遺伝性疾患やがんにおける変異の約三分の一において、結果的に異常な終止コドンが生じるが、mRNA監視機構のひとつであるNMD (nonsense-mediated mRNA decay)により積極的に分解排除される。本研究では、『1) NMD制御因子の新規結合タンパク質を足がかりとした、NMDにおける異常終止コドン識別複合体形成と新生タンパク質解離・リボソーム解離の分子機の解明、2) NMD制御因子の新機能を足がかりとした、細胞ストレスがポスト異常終止コドン識別イベントに与える影響の解明』を行う。これらの解析により、NMDを標的とした革新的新規遺伝性疾患・がん治療開発へ向けた基盤を確立する。

Outline of Final Research Achievements

Nonsense-mediated mRNA decay (NMD) is an mRNA surveillance mechanism that eliminates aberrant mRNAs containing premature termination codons (PTCs). Recent studies revealed the mechanism of PTC recognition. However, post-translational regulation of nascent polypeptides encoded by PTC-containing mRNAs were not well documented. In present study, we found that the inhibition of nascent polypeptides degradation repressed NMD. This finding would provide the novel regulatory tools to modulated NMD activity. Further analysis will promotes the development of new NMD inhibitor.

Academic Significance and Societal Importance of the Research Achievements

本研究により、PTC-mRNAがコードする新生ポリペプチドの運命とNMDによるPTC-mRNA分解が密接に関わっていることが明らかとなった。この成果は、これまでに無い方法でのNMD阻害法の開発や、異常終止コドンを有する遺伝性疾患の新たな治療法開発に繋がる。新生ポリペプチド鎖によるNMD活性の制御は、また、フレームシフトによりPTCを有するmRNAがコードするがん抗原コードペプチドの発現機構の解明にも繋がるものであり、今後の研究の進展を期待している。

Report

(3 results)
  • 2022 Final Research Report ( PDF )
  • 2021 Annual Research Report
  • 2020 Annual Research Report
  • Research Products

    (13 results)

All 2022 2021 2020

All Journal Article (9 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 9 results,  Open Access: 9 results) Presentation (3 results) Book (1 results)

  • [Journal Article] Deficiency of the kidney tubular angiotensin II type1 receptor?associated protein ATRAP exacerbates streptozotocin-induced diabetic glomerular injury via reducing protective macrophage polarization2022

    • Author(s)
      Haruhara Kotaro、Suzuki Toru、Wakui Hiromichi、Azushima Kengo、Kurotaki Daisuke、Kawase Wataru、Uneda Kazushi、Kobayashi Ryu、Ohki Kohji、Kinguchi Sho、Yamaji Takahiro、Kato Ikuma、Ohashi Kenichi、Yamashita Akio、Tamura Tomohiko、Tsuboi Nobuo、Yokoo Takashi、Tamura Kouichi
    • Journal Title

      Kidney International

      Volume: 101 Issue: 5 Pages: 912-928

    • DOI

      10.1016/j.kint.2022.01.031

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Effects of tumor necrosis factor-α inhibition on kidney fibrosis and inflammation in a mouse model of aristolochic acid nephropathy2021

    • Author(s)
      Taguchi Shinya、Azushima Kengo、Yamaji Takahiro、Urate Shingo、Suzuki Toru、Abe Eriko、Tanaka Shohei、Tsukamoto Shunichiro、Kamimura Daisuke、Kinguchi Sho、Yamashita Akio、Wakui Hiromichi、Tamura Kouichi
    • Journal Title

      Scientific Reports

      Volume: 11 Issue: 1 Pages: 23587-23587

    • DOI

      10.1038/s41598-021-02864-1

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Distinct RNA polymerase transcripts direct the assembly of phase-separated DBC1 nuclear bodies in different cell lines2021

    • Author(s)
      Mannen Taro、Goto Masato、Yoshizawa Takuya、Yamashita Akio、Hirose Tetsuro、Hayano Toshiya
    • Journal Title

      Molecular Biology of the Cell

      Volume: 32 Issue: 21

    • DOI

      10.1091/mbc.e21-02-0081

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Tissue-specific expression of the SARS-CoV-2 receptor, angiotensin-converting enzyme 2, in mouse models of chronic kidney disease2021

    • Author(s)
      Tsukamoto Shunichiro、Wakui Hiromichi、Azushima Kengo、Yamaji Takahiro、Urate Shingo、Suzuki Toru、Abe Eriko、Tanaka Shohei、Taguchi Shinya、Yamada Takayuki、Kinguchi Sho、Kamimura Daisuke、Yamashita Akio、Sano Daisuke、Nakano Masayuki、Hashimoto Tatsuo、Tamura Kouichi
    • Journal Title

      Scientific Reports

      Volume: 11 Issue: 1 Pages: 16843-16843

    • DOI

      10.1038/s41598-021-96294-8

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] De novo ATP1A3 variants cause polymicrogyria2021

    • Author(s)
      Miyatake Satoko、Kato Mitsuhiro、Kumamoto Takuma、Hirose Tomonori、他
    • Journal Title

      Science Advances

      Volume: 7 Issue: 13 Pages: 2368-2368

    • DOI

      10.1126/sciadv.abd2368

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Potent mouse monoclonal antibodies that block SARS-CoV-2 infection2021

    • Author(s)
      Guo Youjia、Kawaguchi Atsushi、Takeshita Masaru、Sekiya Takeshi、Hirohama Mikako、Yamashita Akio、Siomi Haruhiko、Murano Kensaku
    • Journal Title

      Journal of Biological Chemistry

      Volume: 296 Pages: 100346-100346

    • DOI

      10.1016/j.jbc.2021.100346

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] New vaccine production platforms used in developing SARS-CoV-2 vaccine candidates2021

    • Author(s)
      Ura Takehiro、Yamashita Akio、Mizuki Nobuhisa、Okuda Kenji、Shimada Masaru
    • Journal Title

      Vaccine

      Volume: 39 Issue: 2 Pages: 197-201

    • DOI

      10.1016/j.vaccine.2020.11.054

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The human papillomavirus E6 protein targets apoptosis-inducing factor (AIF) for degradation2020

    • Author(s)
      Shimada M, Yamashita A, Saito M, Ichino M, Kinjo T, Mizuki N, Klinman DM, Okuda K
    • Journal Title

      Scientific Reports

      Volume: 10 Issue: 1 Pages: 1-14

    • DOI

      10.1038/s41598-020-71134-3

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Shank2 Binds to aPKC and Controls Tight Junction Formation with Rap1 Signaling during Establishment of Epithelial Cell Polarity2020

    • Author(s)
      Sasaki Kazunori、Kojitani Noriko、Hirose Hiroko、Yoshihama Yohei、Suzuki Hidefumi、Shimada Miho、Takayanagi Ayumi、Yamashita Akio、Nakaya Masa-aki、Hirano Hisashi、Takahashi Hidehisa、Ohno Shigeo
    • Journal Title

      Cell Reports

      Volume: 31 Issue: 1 Pages: 107407-107407

    • DOI

      10.1016/j.celrep.2020.02.088

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] mRNA翻訳による生命現象制御の新展開2021

    • Author(s)
      山下 暁朗、藤原 俊伸
    • Organizer
      第44回 日本分子生物学会年会
    • Related Report
      2021 Annual Research Report
  • [Presentation] mRNA監視機構制御因子SMG1キナーゼによる酸化ストレス応答制御機構2021

    • Author(s)
      山下 暁朗
    • Organizer
      第44回 日本分子生物学会年会
    • Related Report
      2021 Annual Research Report
  • [Presentation] mRNA監視機構制御因子SMG1キナーゼによる酸化ストレス応答制御機構2020

    • Author(s)
      山下 暁朗
    • Organizer
      第43回 日本分子生物学会年会
    • Related Report
      2020 Annual Research Report
  • [Book] 疾患原因遺伝子・タンパク質の 解析技術と創薬/診断技術への応用~エピゲノム、トランスクリプトーム、マルチオミクス、オープンデータベースの利活用~2022

    • Author(s)
      藤本明洋ら 86人
    • Total Pages
      530
    • Publisher
      技術情報協会
    • ISBN
      9784861048777
    • Related Report
      2021 Annual Research Report

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Published: 2020-04-28   Modified: 2025-01-30  

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