Mechanism and function of aggregate formation by G-quadruplex RNA-binding protein

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K05704
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 37010:Bio-related chemistry
• Research Institution: Shizuoka University
• Principal Investigator: Oyoshi Takanori 静岡大学, 理学部, 准教授 (80406529)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: グアニン四重鎖 / 核酸結合タンパク質 / 遺伝子発現制御 / ガン / 筋萎縮性側索硬化症

Outline of Final Research Achievements

Recently, G-quadruplex (G4), which is formed in guanine-rich sequences, and G4-binding proteins that contain many arginine-glycine-glycine repeats (RGG) have been reported to be involved in various diseases, cancer, ALS (Amyotrophic lateral sclerosis) and FTD (Frontotemporal dementia). However, the mechanism of G4 recognition by these proteins is unknown. Therefore, I found the novel G4-binding protein in this study and aimed to elucidate their G4 recognition mechanisms. As a result, we found a novel G4-binding protein, Fibrillarin, which contains many RGG sequences. I also analyzed the G4 recognition mechanism of RGG sequences in Fibrillarin and TLS (Transocated in liposarcoma) /FUS (Fused in sarcoma) to elucidate the regulatory mechanism of G4 binding abilities. Furthermore, based on these findings, it will be possible to create various novel artificial G4 DNA-binding proteins from natural G4-binding proteins, which will lead to the development of drugs for G4-related diseases.

Free Research Field

生物化学

Academic Significance and Societal Importance of the Research Achievements

G4は、G4結合タンパク質とともに細胞内で凝集体を形成して、ALS（筋萎縮性側索硬化症）やFTD（前頭側頭型認知症）の原因となることが知られている。また、ゲノム中のプロモーター中にあるG4にG4結合タンパク質が結合することで、下流の遺伝子発現が制御され、細胞のガン化が制御されている。本研究によりG4結合タンパク質によるG4認識機構が明らかになったので、G4とG4結合タンパク質が関与する疾患の機構解明に役立つ。さらに、これらの知見を元に天然のG4結合タンパク質から様々な新規人工G4DNA結合タンパク質の作成が可能になり、G4関連疾患の薬剤開発につながると期待できる。