Development of new cancer therapy targeting the oncogene-induced replication stress response pathway.
| Project/Area Number |
18K07289
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 50020:Tumor diagnostics and therapeutics-related
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| Research Institution | Gunma University |
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Principal Investigator |
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
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| Keywords | 複製ストレス / 発がん / c-Myc / Rad51 / グアニン四重鎖 / Polymerase η / 発がん性複製ストレス / グアニン四重鎖構造 / Myc / G-quadruplex / フォーク保護 / fork reversal / synthetic lethality |
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| Outline of Final Research Achievements |
Activation of oncogene induces slowing or stalling of the replication forks, referred to as “replication stress” (RS), leading to generation of double-strand breaks (DSBs) and genomic instability. Some pathways to overcome RS are useful for neoplastic cells to survive oncogene-induced RS, thus providing potential targets for cancer therapy.
We study the role of Rad51, which is involved in RS response pathways via homologous recombination of DSB repair and regulating progression of replication forks, and Guanine-quadruplex (G4) DNA, four-stranded structures formed by single-stranded G-rich sequences, in oncogene c-Myc (Myc)-induced RS. (1) Rad51 promotes cellular tolerance of Myc-induced RS. (2) Myc activation increases G4 DNA structures and treatment with G4 stabilizing agents enhances Myc-induced DSBs and cell death. (3) Polymerase η (Polη), which prevents Myc-induced RS, might participate in G4-mediated RS in Myc-activating cells.
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| Academic Significance and Societal Importance of the Research Achievements |
Mycファミリー転写因子は代表的がん遺伝子であるが、これを直接標的とする有望な抗がん剤候補は現存せず、新規治療法の開発が期待されている。がんの本質とも言えるDNA損傷応答機構の異常が明らかになるにつれ、これを標的にした分子標的試薬や複数の因子を標的とする「合成致死」を介した治療法の開発が進められている。発がんRS応答機構も標的の一つとして注目され、近年、その成果が報告されつつある。本研究の成果もその一端に位置し、新規がん治療の開発につながることを目標として研究に取り組んでいる。
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Report
(4 results)
Research Products
(8 results)
