Identification and funtional analysis of endonucleases involved in irradiation sensitivity

2014 Fiscal Year Final Research Report

• Project/Area Number: 25740016
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Risk sciences of radiation and chemicals
• Research Institution: Kyoto University
• Principal Investigator: MURAI JUNKO 京都大学, 医学(系)研究科(研究院), 助教 (60532603)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Keywords: DNA修復 / 抗がん剤 / PARP阻害剤 / トポイソメラーゼ / 薬剤耐性

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.

Free Research Field

DNA修復