| Project/Area Number |
18K18200
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 63030:Chemical substance influence on environment-related
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| Research Institution | Hiroshima University |
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Principal Investigator |
Tsuda Masataka 広島大学, 統合生命科学研究科(理), 助教 (00734104)
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| Project Period (FY) |
2018-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2018: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
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| Keywords | トポイソメラーゼ2 / エトポシド / プロテアソーム / DNA修復 |
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| Outline of Final Research Achievements |
Topoisomerase II (TOP2) resolves topologically entwined duplex DNA. It generates a transient DNA double-strand break intermediate, known as TOP2 cleavage complex (TOP2cc), that contains a covalent link between TOP2 and the 5'-terminus of the incised DNA duplex. Etoposide freezes the intermediate and forms irreversible TOP2ccs. Tyrosyl-DNA phosphodiesterase 2 (TDP2) is thought to repair irreversible TOP2ccs by hydrolyzing the phosphodiester bond between TOP2 and DNA after the proteasomal degradation of trapped TOP2ccs. In this study, I revealed novel proteasome-independent mechanisms for the repair of Topoisomerase2 (TOP2) cleavage complex.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究から、新規のTOP2cc除去経路の存在が明らかになった。この除去経路に、TDP2というタンパク質が中心的な役割を果たすことが分かった。これまで、TDP2はプロテアソームというタンパク質複合体と協調して働くことが分かっていたので、プロテアソーム阻害剤とエトポシドの暴露が抗がん治療の効果を高めると考えられていた。本研究成果から、TDP2阻害剤とエトポシドを併用した治療法の重要性が明らかになった。
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