Analysis of Rad17 ATPase for Targeting the DNA Damage Response

2023 Fiscal Year Final Research Report

• Project/Area Number: 19K07079
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47030:Pharmaceutical hygiene and biochemistry-related
• Research Institution: Chiba University
• Principal Investigator: Fukumoto Yasunori 千葉大学, 大学院薬学研究院, 講師 (10447310)
• Co-Investigator(Kenkyū-buntansha): 中山 祐治 京都薬科大学, 薬学部, 教授 (10280918)
• Project Period (FY): 2019-04-01 – 2024-03-31
• Keywords: DNA損傷応答 / 細胞周期 / 細胞周期チェックポイント / 翻訳後修飾 / タンパク質分解 / Rad17 / 9-1-1複合体 / ATR

Outline of Final Research Achievements

DNA damage response (DDR) is a critical mechanism involved in cancer suppression and treatment. In this study, we focused on the structure-activity relationship of Rad17, a representative protein that regulates DDR, and obtained findings that could lead to the development of DDR-targeted therapeutics. We elucidated that the iVERGE domain located at the C-terminus of Rad17 and its phosphorylation are essential for Rad17's functionality. Furthermore, we discovered the spatial regulation of Rad17 within cells, particularly noting that its nuclear translocation promotes proteasome-dependent degradation of Rad17 protein. This research has provided significant insights into the regulatory mechanisms of Rad17 and its associated factors, yielding results that contribute to the development of molecular targeted drugs aimed at DDR.

Free Research Field

生物系薬学

Academic Significance and Societal Importance of the Research Achievements

本研究では、Rad17がKYxxLモチーフに加えて、iVERGEを二つ目の9-1-1複合体との相互作用ドメインとして持つことを示した。KYxxLとiVERGEそれぞれの制御機構を解析することで、DNA損傷応答の詳細な制御機構が明らかになると期待される。また、これはDDRを標的とする新規分子標的薬の開発において、Rad17と9-1-1複合体との相互作用を標的とする創薬に繋がる成果である。さらに、Rad17の細胞内局在の制御や二つのD-boxの存在が明らかとなり、新規分子標的の創出やDDRを標的とする抗がん剤の新規スクリーニング系の構築に貢献することが期待される。