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Identification and characterization of DNA/RNA heteroduplex oligonucleotide cleaving enzyme

Research Project

Project/Area Number 18K05550
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 38060:Applied molecular and cellular biology-related
Research InstitutionInstitute of Physical and Chemical Research (2019-2020)
National Cancer Center Japan (2018)

Principal Investigator

Asada Ken  国立研究開発法人理化学研究所, 革新知能統合研究センター, 研究員 (70773414)

Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywords核酸医薬 / 遺伝子発現制御 / ヌクレアーゼ / ヘテロ2本鎖核酸 / 一本鎖核酸 / 核酸医療 / DNA/RNAヘテロ核酸 (HDO) / ヘテロ核酸を用いた遺伝子制御
Outline of Final Research Achievements

A tocopherol conjugated DNA/RNA heteroduplex oligonucleotide (Toc-HDO) as a new type of drug. Toc-HDO is more potent, stable, and efficiently taken up by the target tissues. However, the detailed mechanisms of Toc-HDO, including its binding proteins, are unknown. Here, we developed native gel shift assays with fluorescence-labeled nucleic acids samples extracted from mice livers. These assays revealed two Toc-HDO binding proteins, annexin A5 (ANXA5) and carbonic anhydrase 8 (CA8). Later, we identified two more proteins, apurinic/apyrimidinic endodeoxyribonuclease 1 (APEX1) and flap structure-specific endonuclease 1 (FEN1) by data mining. All four proteins regulated Toc-HDO activity in Hepa1-6, mouse hepatocellular cells. In vitro binding assays and pull-down assays demonstrated the protein binding to the Toc-HDO in a biological environment. Taken together, our findings provide a brand new molecular biological insight as well as future directions for HDO-based disease therapy.

Academic Significance and Societal Importance of the Research Achievements

本研究グループはこれまでに独自に開発した核酸医薬であるHDOが、非常に高い遺伝子発現抑制効果を示すことを報告しています。しかしながら、HDOの細胞内の作用分子メカニズムは解明されていませんでした。今回研究グループは、HDOに特異的な結合タンパク質を複数同定することに成功しました。同定したタンパク質は、塩基配列に関わらず13~16塩基対の短いDNA/RNAに選択的に結合できることを見出しました。同定した結合タンパク質が、HDOの活性制御に重要な働きをしていることを明らかにしました。
HDOの作用メカニズムの解明により、今後は効果が高く副作用の少ない核酸医薬の開発につながるものと期待されます。

Report

(4 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Research-status Report
  • 2018 Research-status Report
  • Research Products

    (20 results)

All 2021 2020 Other

All Journal Article (10 results) (of which Int'l Joint Research: 5 results,  Peer Reviewed: 10 results,  Open Access: 10 results) Presentation (7 results) Book (1 results) Remarks (2 results)

  • [Journal Article] Shadow Estimation for Ultrasound Images Using Auto-Encoding Structures and Synthetic Shadows2021

    • Author(s)
      Yasutomi Suguru、Arakaki Tatsuya、Matsuoka Ryu、Sakai Akira、Komatsu Reina、Shozu Kanto、Dozen Ai、Machino Hidenori、Asada Ken、Kaneko Syuzo、Sekizawa Akihiko、Hamamoto Ryuji、Komatsu Masaaki
    • Journal Title

      Applied Sciences

      Volume: 11 Issue: 3 Pages: 1127-1127

    • DOI

      10.3390/app11031127

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Detection of Cardiac Structural Abnormalities in Fetal Ultrasound Videos Using Deep Learning2021

    • Author(s)
      Komatsu Masaaki、Sakai Akira、Komatsu Reina、Matsuoka Ryu、Yasutomi Suguru、Shozu Kanto、Dozen Ai、Machino Hidenori、Hidaka Hirokazu、Arakaki Tatsuya、Asada Ken、Kaneko Syuzo、Sekizawa Akihiko、Hamamoto Ryuji
    • Journal Title

      Applied Sciences

      Volume: 11 Issue: 1 Pages: 371-371

    • DOI

      10.3390/app11010371

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Separation-related rapid nuclear transport of DNA/RNA heteroduplex oligonucleotide: unveiling distinctive intracellular trafficking2021

    • Author(s)
      Ono Daisuke、Asada Ken、Yui Daishi、Sakaue Fumika、Yoshioka Kotaro、Nagata Tetsuya、Yokota Takanori
    • Journal Title

      Molecular Therapy - Nucleic Acids

      Volume: 23 Pages: 1360-1370

    • DOI

      10.1016/j.omtn.2020.11.022

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Model-Agnostic Method for Thoracic Wall Segmentation in Fetal Ultrasound Videos2020

    • Author(s)
      Shozu Kanto、Komatsu Masaaki、Sakai Akira、Komatsu Reina、Dozen Ai、Machino Hidenori、Yasutomi Suguru、Arakaki Tatsuya、Asada Ken、Kaneko Syuzo、Matsuoka Ryu、Nakashima Akitoshi、Sekizawa Akihiko、Hamamoto Ryuji
    • Journal Title

      Biomolecules

      Volume: 10 Issue: 12 Pages: 1691-1691

    • DOI

      10.3390/biom10121691

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Application of Artificial Intelligence Technology in Oncology: Towards the Establishment of Precision Medicine2020

    • Author(s)
      Hamamoto Ryuji、Suvarna Kruthi、Yamada Masayoshi、Kobayashi Kazuma、Shinkai Norio、Miyake Mototaka、Takahashi Masamichi、Jinnai Shunichi、Shimoyama Ryo、Sakai Akira、Takasawa Ken、Bolatkan Amina、Shozu Kanto、Dozen Ai、Machino Hidenori、Takahashi Satoshi、Asada Ken、Komatsu Masaaki、Sese Jun、Kaneko Syuzo
    • Journal Title

      Cancers

      Volume: 12 Issue: 12 Pages: 3532-3532

    • DOI

      10.3390/cancers12123532

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Two Secreted Proteoglycans, Activators of Urothelial Cell?Cell Adhesion, Negatively Contribute to Bladder Cancer Initiation and Progression2020

    • Author(s)
      Papadaki V, Asada K, Watson JK, Tamura T, Leung A, Hopkins J, Dellett M, Sasai N, Davaapil H, Nik-Zainal S, Longbottom R, Nakakido M, Torii R, Veerakumarasivam A, Kaneko S, Sagoo MS, Murphy G, Mitani A, Tsumoto K, Kelly JD, Hamamoto R, Ohnuma SI
    • Journal Title

      Cancers

      Volume: 12 Issue: 11 Pages: 3362-3362

    • DOI

      10.3390/cancers12113362

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Image Segmentation of the Ventricular Septum in Fetal Cardiac Ultrasound Videos Based on Deep Learning Using Time-Series Information2020

    • Author(s)
      Dozen Ai、Komatsu Masaaki、Sakai Akira、Komatsu Reina、Shozu Kanto、Machino Hidenori、Yasutomi Suguru、Arakaki Tatsuya、Asada Ken、Kaneko Syuzo、Matsuoka Ryu、Aoki Daisuke、Sekizawa Akihiko、Hamamoto Ryuji
    • Journal Title

      Biomolecules

      Volume: 10 Issue: 11 Pages: 1526-1526

    • DOI

      10.3390/biom10111526

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Predicting Deep Learning Based Multi-Omics Parallel Integration Survival Subtypes in Lung Cancer Using Reverse Phase Protein Array Data2020

    • Author(s)
      Takahashi Satoshi、Asada Ken、Takasawa Ken、Shimoyama Ryo、Sakai Akira、Bolatkan Amina、Shinkai Norio、Kobayashi Kazuma、Komatsu Masaaki、Kaneko Syuzo、Sese Jun、Hamamoto Ryuji
    • Journal Title

      Biomolecules

      Volume: 10 Issue: 10 Pages: 1460-1460

    • DOI

      10.3390/biom10101460

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Critical Roles of N6-Methyladenosine (m6A) in Cancer and Virus Infection2020

    • Author(s)
      Asada Ken、Bolatkan Amina、Takasawa Ken、Komatsu Masaaki、Kaneko Syuzo、Hamamoto Ryuji
    • Journal Title

      Biomolecules

      Volume: 10 Issue: 7 Pages: 1071-1071

    • DOI

      10.3390/biom10071071

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Uncovering Prognosis-Related Genes and Pathways by Multi-Omics Analysis in Lung Cancer2020

    • Author(s)
      Asada Ken、Kobayashi Kazuma、Joutard Samuel、Tubaki Masashi、Takahashi Satoshi、Takasawa Ken、Komatsu Masaaki、Kaneko Syuzo、Sese Jun、Hamamoto Ryuji
    • Journal Title

      Biomolecules

      Volume: 10 Issue: 4 Pages: 524-524

    • DOI

      10.3390/biom10040524

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] Uncovering Prognosis-related Genes and Pathways by Multi-omics Analysis in Lung Adenocarcinoma2020

    • Author(s)
      浅田健, 小林和馬, 高橋慧, 高澤建, 小松正明, 金子修三, 浜本隆二
    • Organizer
      第79回日本癌学会学術総会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Clinical epigenetic analysis with robotics in ovarian cancer2020

    • Author(s)
      小松正明, 金子修三, 浅田健, 吉田裕, 加藤友康, 浜本隆二
    • Organizer
      第79回日本癌学会学術総会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Intefrative multi-omics analysis of multistage tumorigenesis in high-grade serous ovarian cancer2020

    • Author(s)
      同前愛, 小松正明, 町野英徳, 中村康平, 金子修三, 生水貫人, 浅田健, 千代田達幸, 中山健太郎, 青木大輔, 京哲, 浜本隆二
    • Organizer
      第79回日本癌学会学術総会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Biological mechanisms of PRELP in ovarian cancer2020

    • Author(s)
      生水貫人, 小松正明, 金子修三, 同前愛, 町野英徳, 中島彰俊, 齋藤滋, 浅田健, 浜本隆二
    • Organizer
      第79回日本癌学会学術総会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Overexpression of METTL6 is involved in human hepatocellular carcinoma2020

    • Author(s)
      ボラトカン アミーナ, 金子修三, 浅田健, 浜本隆二
    • Organizer
      第79回日本癌学会学術総会
    • Related Report
      2020 Annual Research Report
  • [Presentation] LKB1-MARK3 axis is a novel stress-activated cell cycle checkpoint and sysregulated in high-grade serous obarian cancer2020

    • Author(s)
      町野英徳, 金子修三, 小松正明, 浅田健, 同前愛, 生水貫人, 浜本隆二
    • Organizer
      第79回日本癌学会学術総会
    • Related Report
      2020 Annual Research Report
  • [Presentation] 肺がん予後予測を志向したマルチオミックス解析2020

    • Author(s)
      浅田健、小林和馬、高橋慧、高澤建、小松正明、金子修三、浜本隆二
    • Organizer
      第2回日本メディカルAI学会学術集会
    • Related Report
      2020 Annual Research Report
  • [Book] 医学のあゆみ AIが切り拓く未来の医療2020

    • Author(s)
      浅田健, 浜本隆二
    • Total Pages
      919
    • Publisher
      医歯薬出版
    • Related Report
      2020 Annual Research Report
  • [Remarks] 「 ヘテロ核酸医薬による遺伝子発現制御メカニズムを解明 」― より有効な核酸医薬のデザインが可能に

    • URL

      https://www.amed.go.jp/news/release_20210430-03.html

    • Related Report
      2020 Annual Research Report
  • [Remarks] ヘテロ核酸医薬による遺伝子発現制御メカニズムを解明

    • URL

      https://www.tmd.ac.jp/topics_detail/id=20210430-1

    • Related Report
      2020 Annual Research Report

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Published: 2018-04-23   Modified: 2022-01-27  

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