Inhibition of the ATR kinase enhances 5-FU sensitivity independently of nonhomologous end-joining and homologous recombination repair pathways.

• Material Type: 博士論文
• ISSN: 0021-9258
• Title: Inhibition of the ATR kinase enhances 5-FU sensitivity independently of nonhomologous end-joining and homologous recombination repair pathways.
• Volume: 295 37
• Author/Editor: Ito, Soichiro S; Nakagawa, Yosuke; Matsubayashi, Masaya; Sakaguchi, Yoshihiko M; Kobashigawa, Shinko; Matsui, Takeshi K; Nanaura, Hitoki; Nakanishi, Mari; Kitayoshi, Fumika; Kikuchi, Sotaro; Kajihara, Atsuhisa; Tamaki, Shigehiro; Sugie, Kazuma; Kashino, Genro; Takahashi, Akihisa; Hasegawa, Masatoshi; Mori, Eiichiro; Kirita, Tadaaki
• Author Heading: Ito, Soichiro S; Nakagawa, Yosuke; Matsubayashi, Masaya; Sakaguchi, Yoshihiko M; Kobashigawa, Shinko; Matsui, Takeshi K; Nanaura, Hitoki; Nakanishi, Mari; Kitayoshi, Fumika; Kikuchi, Sotaro; Kajihara, Atsuhisa; Tamaki, Shigehiro; Sugie, Kazuma; Kashino, Genro; Takahashi, Akihisa; Hasegawa, Masatoshi; Mori, Eiichiro; Kirita, Tadaaki
• Publication, Distribution, etc.: Elsevier
• Publication Date: 2020-09-11; 295 37
• Publication Date (W3CDTF): 2020-09-11
• Alternative Title: ATR阻害は非相同末端結合および相同組換え修復と非依存的に5-FUを増感する
• Periodical title: The Journal of biological chemistry
• Degree grantor/type: 奈良県立医科大学
• Date Granted: 2021-03-15
• Date Granted (W3CDTF): 2021-03-15
• Dissertation Number: 甲第791号
• Degree Type: 博士（医学）
• Conferring No. (Dissertation): 甲第791号
• Text Language Code: eng
• Subject Heading: ATR serine/threonine kinase; 5-fluorouracil; cell-cycle checkpoint; DNA double-strand breaks; homologous recombination; BRCA2; cancer; apoptosisantineoplastic agent; chemotherapy; DNA repair; DNA damage response; cell cycle; anticancer drug
• Target Audience: 一般
• Note (General): type:Thesis; The anticancer agent 5-fluorouracil (5-FU) is cytotoxic and often used to treat various cancers. 5-FU is thought to inhibit the enzyme thymidylate synthase, which plays a role in nucleotide synthesis and has been found to induce single- and double-strand DNA breaks. ATR Ser/Thr kinase (ATR) is a principal kinase in the DNA damage response and is activated in response to UV- and chemotherapeutic drug-induced DNA replication stress, but its role in cellular responses to 5-FU is unclear. In this study, we examined the effect of ATR inhibition on 5-FU sensitivity of mammalian cells. Using immunoblotting, we found that 5-FU treatment dose-dependently induced the phosphorylation of ATR at the autophosphorylation site Thr-1989 and thereby activated its kinase. Administration of 5-FU with a specific ATR inhibitor remarkably decreased cell survival, compared with 5-FU treatment combined with other major DNA repair kinase inhibitors. Of note, the ATR inhibition enhanced induction of DNA double-strand breaks and apoptosis in 5-FU-treated cells. Using gene expression analysis, we found that 5-FU induced the activation of the intra-S cell-cycle checkpoint. Cells lacking BRCA2 were sensitive to 5-FU in the presence of ATR inhibitor. Moreover, ATR inhibition enhanced the efficacy of the 5-FU treatment, independently of the nonhomologous end-joining and homologous recombination repair pathways. These findings suggest that ATR could be a potential therapeutic target in 5-FU-based chemotherapy.; 博士（医学）・甲第791号・令和3年3月15日; © 2020 Ito et al. Published under exclusive license by The American Society for Biochemistry and Molecular Biology, Inc.; This is an Open Access article under the CC BY license(https://creativecommons.org/licenses/by/4.0/).; identifier:The Journal of biological chemistry Vol.295 No.37 p.12946-12961 (2020 Sep); identifier:00219258; identifier:http://ginmu.naramed-u.ac.jp/dspace/handle/10564/3915; identifier:The Journal of biological chemistry, 295(37): 12946-12961
• DOI: info:doi/10.1074/jbc.RA120.013726; https://doi.org/info:doi/10.1074/jbc.RA120.013726
• Persistent ID (NDL): info:ndljp/pid/12070972; https://dl.ndl.go.jp/pid/12070972
• Collection: 障害者向け資料
• Collection (Materials For Handicapped People:1): テキストデータ
• Collection (particular): 国立国会図書館デジタルコレクション > デジタル化資料 > 博士論文; https://dl.ndl.go.jp/collections/A00014
• Acquisition Basis: 博士論文（自動収集）
• Date Accepted (W3CDTF): 2022-02-06T04:33:19+09:00
• Format (IMT): application/pdf
• Access Restrictions: 国立国会図書館内限定公開
• Service for the Digitized Contents Transmission Service: 図書館・個人送信対象外
• Availability of remote photoduplication service: 可
• Periodical Title (URI): http://hdl.handle.net/10564/3915
• Data Provider (Database): 国立国会図書館 : 国立国会図書館デジタルコレクション; https://dl.ndl.go.jp

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