Elucidation of the mechanism of novel regulators of tumor suppressor microRNA let-7 and search for novel therapeutic targets

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K16794
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 50020:Tumor diagnostics and therapeutics-related
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Kurimoto Ryota 東京医科歯科大学, 大学院医歯学総合研究科, 講師 (10753957)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: RNA / マイクロRNA / RNA修飾 / CLIP

Outline of Final Research Achievements

Let-7 functions as a core tumor suppressor microRNA in many malignancies. Although let-7 is regulated by RNA-binding proteins (RBPs), the full extent of this regulation is unknown.
In this study, we applied a luciferase reporter to target all RBPs and functionally screened for genes that regulate let-7 expression, and identified several genes including a new regulator, TruB1. Biochemical analysis and comprehensive analysis using next-generation sequencers revealed that TruB1, a tRNA-modifying enzyme, binds specifically to let-7 and positively regulates it in an enzyme activity-independent manner. We also found that this suppresses tumor growth potential.

Free Research Field

分子生物学

Academic Significance and Societal Importance of the Research Achievements

このtRNA修飾酵素TruB1が、その酵素活性とは独立してlet-7を上昇させることを明らかにした。この機構は、酵素活性という既存の機能のみに注目した研究方法では見出すことが困難であったが、microRNAの機能的スクリーニングとRNAへの結合を網羅的に解析するCLIP法の組み合わせによって初めて見出すことが可能となった。ゲノム遺伝学や既存の治療法、検査法のみでは解析の困難なエピトランスクリプトームの研究手法の選択肢を示すものである。