A study of mechanism of resolving DNA replication stress by long non-coding RNA in cancer cell

2022 Fiscal Year Final Research Report

• Project/Area Number: 20H03511
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Nagoya University
• Principal Investigator: Kondo Yutaka 名古屋大学, 医学系研究科, 教授 (00419897)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 非翻訳RNA / がん / DNA損傷 / R-loop

Outline of Final Research Achievements

Oncogene-induced DNA replication stress (RS) and consequent pathogenic R-loop formation is known to impede S phase progression. Nonetheless, cancer cells continuously proliferate under such high-stressed conditions through incompletely understood mechanisms. We studied taurine upregulated gene 1 (TUG1) long noncoding RNA (lncRNA). Under RS conditions, TUG1 was rapidly upregulated via activation of the ATR-CHK1 signaling pathway, interacted with RPA and DHX9, and engaged in resolving R-loops at certain loci, particularly at the CA repeat microsatellite loci. Depletion of TUG1 led to an overabundant R-loops and enhanced RS, leading to substantial inhibition of tumor growth. Our data reveal a novel role of TUG1 as an indispensable molecule for resolving the problem of R-loop accumulation in cancer cells and a strong rationale for targeting TUG1 as a potent therapeutic approach for cancer treatment.

Free Research Field

腫瘍生物学

Academic Significance and Societal Importance of the Research Achievements

本研究結果を基盤として、TUG1に対する核酸医薬は、がんの新規治療薬として企業との共同開発に至っている。TUG1に対する核酸医薬が実用化に至れば、核酸医薬としての先駆的位置づけに加えて、lncRNAというこれまで治療標的とされてこなかった分子を標的とした新しいクラスの治療法になる。