2021 Fiscal Year Final Research Report

Chemical approaches to understand the complex mechanism of nucleotide excision repair

Research Project

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Project/Area Number	19H04265
Research Category	Grant-in-Aid for Scientific Research (B)
Allocation Type	Single-year Grants
Section	一般
Review Section	Basic Section 63020:Radiation influence-related
Research Institution	Kanazawa University
Principal Investigator	MATSUNAGA Tsukasa 金沢大学, 薬学系, 教授 (60192340)
Co-Investigator(Kenkyū-buntansha)	若杉光生金沢大学, 薬学系, 准教授 (80345595) 後藤享子金沢大学, 薬学系, 准教授 (50180245) 猪部学国際医療福祉大学, 福岡薬学部, 教授 (10312414) 松浦顕教金沢大学, 薬学系, 博士研究員 (50836096)
Project Period (FY)	2019-04-01 – 2022-03-31
Keywords	ヌクレオチド除去修復 / ケミカルバイオロジー / 阻害剤 / タンパク質分解誘導剤 / 近位依存性ビオチン標識法
Outline of Final Research Achievements	To understand the complex mechanism of human nucleotide excision repair (NER), we have employed two types of chemical biology approaches. First of all, we have analyzed the molecular mechanism underlying the poly-ubiquitination reaction induced by a small-molecule ERCC1 degrader. We also revealed that other kinds of small-molecule NER inhibitor enhance the physical interaction between XPC and p62 subunit of TFIIH. Furthermore, we have successfully introduced a proximity-dependent biotin identification (BioID) method to isolate and analyze the intermediate protein-complexes at various steps of NER. Using this approach, we have identified some of known NER factors as well as novel proteins possibly involved in NER.
Free Research Field	分子細胞生物学
Academic Significance and Societal Importance of the Research Achievements	本研究では、これまでに同定した複数のNER阻害化合物の作用機序を概ね明らかにし、今後のNER研究で有用なツールになることを示すとともに、新たに導入したBioID法が画期的なNER解析技術となることを示した学術的意義は大きい。特に、両者を組み合わせることで、複雑な多段階NER反応のステップごとの中間複合体を単離・解析することができ、それらの情報をつなぎ合わせることでNERの動的メカニズムの理解につながる発展性はインパクトがあり、本研究成果の社会的意義は大きい。