A study of mechanism of resolving DNA replication stress by long non-coding RNA in cancer cell
| Project/Area Number |
20H03511
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Review Section |
Basic Section 50010:Tumor biology-related
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| Research Institution | Nagoya University |
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Principal Investigator |
Kondo Yutaka 名古屋大学, 医学系研究科, 教授 (00419897)
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| Project Period (FY) |
2020-04-01 – 2023-03-31
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| Project Status |
Completed (Fiscal Year 2022)
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| Budget Amount *help |
¥17,940,000 (Direct Cost: ¥13,800,000、Indirect Cost: ¥4,140,000)
Fiscal Year 2022: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2020: ¥8,580,000 (Direct Cost: ¥6,600,000、Indirect Cost: ¥1,980,000)
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| Keywords | 非翻訳RNA / がん / DNA損傷 / R-loop / DNA複製ストレス / ドラッグデリバリー / 長鎖非翻訳RNA / 複製ストレス / エピゲノム |
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| Outline of Research at the Start |
急速に増殖するがん細胞にとってDNA複製ストレスの調節は必須である。本研究では複製ストレスの調節に長鎖非翻訳RNA (lncRNA) TUG1が関与することに着目し、その機能の詳細および治療への応用について研究を進める。複製ストレスの調節機構は、がん細胞が恒常的に分裂・増殖をするための分子基盤として必須であり、がん細胞の“アキレス腱”とも言えることから、本調節機構を治療標的とすることは合理的アプローチであり、革新的がん治療法の開発が期待できる。
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| Outline of Final Research Achievements |
Oncogene-induced DNA replication stress (RS) and consequent pathogenic R-loop formation is known to impede S phase progression. Nonetheless, cancer cells continuously proliferate under such high-stressed conditions through incompletely understood mechanisms. We studied taurine upregulated gene 1 (TUG1) long noncoding RNA (lncRNA). Under RS conditions, TUG1 was rapidly upregulated via activation of the ATR-CHK1 signaling pathway, interacted with RPA and DHX9, and engaged in resolving R-loops at certain loci, particularly at the CA repeat microsatellite loci. Depletion of TUG1 led to an overabundant R-loops and enhanced RS, leading to substantial inhibition of tumor growth. Our data reveal a novel role of TUG1 as an indispensable molecule for resolving the problem of R-loop accumulation in cancer cells and a strong rationale for targeting TUG1 as a potent therapeutic approach for cancer treatment.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究結果を基盤として、TUG1に対する核酸医薬は、がんの新規治療薬として企業との共同開発に至っている。TUG1に対する核酸医薬が実用化に至れば、核酸医薬としての先駆的位置づけに加えて、lncRNAというこれまで治療標的とされてこなかった分子を標的とした新しいクラスの治療法になる。
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Report
(4 results)
Research Products
(28 results)
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[Journal Article] Characteristic DNA methylation profiles of chorionic villi in recurrent miscarriage2022
Author(s)
Matsumoto Y, Shinjo K, Mase S, Fukuyo M, Aoki K, Ozawa F, Yoshihara H, Goto S, Kitaori T, Ozaki Y, Takahashi S, Kaneda A, Sugiura-Ogasawara M, Kondo Y.
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Journal Title
Scientific Reports
Volume: 12
Issue: 1
Pages: 11673-11673
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Cancer-Specific Targeting of Taurine-Upregulated Gene 1 Enhances the Effects of Chemotherapy in Pancreatic Cancer2021
Author(s)
Tasaki Y, Suzuki M, Katsushima K, Shinjo K, Iijima K, Murofushi Y, Naiki-Ito A, Hayashi K, Qiu C, Takahashi A, Tanaka Y, Kawaguchi T, Sugawara M, Kataoka T, Naito M, Miyata K, Kataoka K, Noda T, Gao W, Kataoka H, Takahashi S, Kimura K, Kondo Y.
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Journal Title
Cancer Research
Volume: -
Issue: 7
Pages: 1654-1666
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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