Identification and funtional analysis of endonucleases involved in irradiation sensitivity
| Project/Area Number |
25740016
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Multi-year Fund |
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| Research Field |
Risk sciences of radiation and chemicals
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| Research Institution | Kyoto University |
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Principal Investigator |
MURAI JUNKO 京都大学, 医学(系)研究科(研究院), 助教 (60532603)
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| Project Period (FY) |
2013-04-01 – 2015-03-31
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| Project Status |
Completed (Fiscal Year 2014)
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| Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2014: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Fiscal Year 2013: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
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| Keywords | DNA修復 / 抗がん剤 / PARP阻害剤 / トポイソメラーゼ / 薬剤耐性 / がん / 相同組み替え / DNAダメージ / ヌクレアーゼ / 放射線 / 抗がん治療 / DNA損傷 / 併用療法 / PARP |
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| Outline of Final Research Achievements |
In this study, we revealed novel function of a DNA repair gene TDP1 (tyrosyl-DNA phosphodiesterase) that is involved in the repair of DNA damages induced by irradiation and chemotherapy. Our findings would lead to a novel strategy to overcome cancers, because the combination of irradiation or chemotherapy in TDP1 deficient cancer cells or TDP1 inhibitors (under development) would augment the cytotoxicity of the treatment.
Furthermore, we have discovered a novel mechanism of action for PARP inhibitors, recently developed anti-cancer agents. Although PARP inhibitors with highly catalytic PARP inhibition tend to be considered equivalent, we found that the potency of the new mechanism of action named “PARP-trapping” is markedly (more than 1,000 folds) different among five clinical PARP inhibitors and that the PARP-trapping potency corresponds to the cytotoxicity of each drug. We also revised the strategy of drug combination with PARP inhibitors based on the new mechanisms.
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Report
(3 results)
Research Products
(14 results)
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[Journal Article] SLFN11 is a transcriptional target of EWS-FLI1 and a determinant of drug response in Ewing's sarcoma2015
Author(s)
Tang, S. W. Bilke, S. Cao, L. Murai, J. Sousa, F. G. Yamade, M. Rajapakse, V. Varma, S. Helman, L. J. Khan, J. Meltzer, P. S. Pommier, Y.
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Journal Title
Clin Cancer Res
Volume: N/A
Issue: 18
Pages: 4184-4193
DOI
Related Report
Peer Reviewed
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[Journal Article] The POLD3 subunit of DNA polymerase δ can promote translesion synthesis independently of DNA polymerase ζ.2015
Author(s)
Hirota K, Yoshikiyo K, Guilbaud G, Tsurimoto T, Murai J, Tsuda M, Phillips L, Narita T, Nishihara K, Kobayashi K, Yamada K, Nakamura J, Pommier Y, Lehmann, A, Sale J, Takeda S
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Journal Title
Nucleic Acids Res.
Volume: 43
Issue: 3
Pages: 1671-1683
DOI
NAID
Related Report
Peer Reviewed / Open Access / Acknowledgement Compliant
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[Journal Article] Identification of novel PARP inhibitors using a cell-based TDP1 inhibitory assay in a quantitative high-throughput screening platform.2014
Author(s)
Murai J, Marchand C, Shahane SA, Sun H, Huang R, Zhang Y, Chergui A, Ji J, Doroshow JH, Jadhav A, Takeda S, Xia M, Pommier Y
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Journal Title
DNA Repair
Volume: 21
Pages: 177-182
DOI
Related Report
Peer Reviewed
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[Journal Article] PARP1-TDP1 coupling for the repair of topoisomerase I-induced DNA damage.2014
Author(s)
Das BB, Huang SY, Murai J, Rehman I, Ame JC, Sengupta S, Das SK, Majumdar P, Zhang H, Biard D, Majumder HK, Schreiber V, Pommier Y.
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Journal Title
Nucleic Acids Research
Volume: 42
Issue: 7
Pages: 4435-4449
DOI
Related Report
Peer Reviewed
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