Molecular mechanisms of mammalian endogenous RNA-dependent DNA base modification and disease pathogenesis due to dysregulation

2021 Fiscal Year Final Research Report

• Project/Area Number: 19H03159
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 43010:Molecular biology-related
• Research Institution: Tokyo University of Science
• Principal Investigator: Sakurai Masayuki 東京理科大学, 研究推進機構生命医科学研究所, 准教授 (80809236)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: イノシン / ADAR / A-to-I エディティング / DNA 編集 / RNA編集 / RNA editing / エピトランスクリプトーム / 塩基修飾

Outline of Final Research Achievements

In this study, we have found that an enzyme named ADAR, originally discovered and considered as a double-stranded RNA-specific adenosine deaminase, can edit adenosine (A) into inosine (I) of RNA and even surprisingly, of DNA in RNA:DNA hybrid double strand. The fact indicates that even mammalian cells have endogenous genomic DNA editing system, which is guided by RNA:DNA hybrid strand formation and the ADAR. Since inosine can base pairs with cytidine(C), A-to-I editing has a similar effect on genetic information to mutation into guanosine (G). Thus, the A-to-I DNA editing can be considered an endogenous active DNA mutating or repairing mechanism. We revealed that A-to-I DNA editing activity by the ADAR was required for cell survival. Furthermore, we have invented a new technique for detecting and quantifying overlooked inosines in nucleic acids.

Free Research Field

核酸分子生物学

Academic Significance and Societal Importance of the Research Achievements

近年CRISPRに代表される，ガイド核酸を用いた人為的ゲノム編集技術が広く利用されている一方，これまで哺乳動物細胞が内在的に備えるガイド核酸によるゲノム編集機構は未発見であった。研究対象であるA-to-I DNA編集はその初のものとなり，見過ごされてきたDNAの変異あるいは修復を担うことが想定され，今回はその一例を解明し報告した。その制御破綻はDNA配列異常を引き起こすため，がん化や遺伝子疾患の原因となりうる。本研究の成果の一つとして，そのようなA-to-I DNA編集部位がこれまで同定不可能であったものを打破し，その機序解明を加速するものである。