PO.MCB04.02 · 分子与细胞生物学
lncRNA TUG1通过RNA-蛋白相互作用增强解旋酶介导的R-loop解离
The lncRNA TUG1 enhances helicase-mediated R-loop resolution through RNA-protein interaction
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
长链非编码RNA（lncRNA）是基因组稳定性的新兴调控因子。牛磺酸上调基因1（TUG1）在癌细胞中高表达，并在复制应激下由ATR-CHK1信号快速诱导。我们此前表明，TUG1与复制蛋白A以及DEAE/DEAD盒解旋酶DHX9相互作用，从而能够解离致病性R-loop并支持癌细胞增殖。为拓展我们对TUG1功能的理解，我们采用基于CRISPR的RNA-蛋白检测方法结合蛋白质组学分析，全面刻画了其相互作用蛋白。在复制应激下，一组保守的R-loop相关因子（包括RNA解旋酶）得到富集，提示TUG1-蛋白相互作用响应R-loop累积而发生动态重塑。结构和生化分析进一步提示，TUG1通过直接的RNA-蛋白结合促进解旋酶介导的R-loop解离。总之，我们的发现揭示了一条复制应激响应性的TUG1-解旋酶轴，其通过促进R-loop解离维持基因组完整性。鉴于靶向TUG1的反义寡核苷酸已进入临床试验，本研究提供了支持TUG1作为有前景的癌症治疗靶点的机制基础。
查看英文原文 English abstract
Long non-coding RNAs (lncRNAs) are emerging regulators of genome stability. Taurine upregulated gene 1 (TUG1) is highly expressed in cancer cells and rapidly induced by ATR-CHK1 signaling under replication stress. We previously showed that TUG1 interacts with replication protein A and the DEAE/DEAD-box helicase DHX9, enabling the resolution of pathogenic R-loops and supporting cancer cell proliferation. To expand our understanding of TUG1 function, we comprehensively profiled its interacting proteins using a CRISPR-based RNA-protein detection approach coupled with proteomic analysis. A conserved set of R-loop-associated factors, including RNA helicases, was enriched under replication stress, suggesting dynamic remodeling of TUG1-protein interactions in response to R-loop accumulation. Structural and biochemical analyses further suggested that TUG1 promotes helicase-mediated R-loop resolution through direct RNA-protein association. Collectively, our findings uncover a replication stress-responsive TUG1-helicase axis that maintains genome integrity by promoting R-loop resolution. Given that TUG1-targeting antisense oligonucleotides are already advancing into clinical trials, this study provides a mechanistic foundation supporting TUG1 as a promising therapeutic target for cancer treatment.
利益披露 Disclosure
S. Mimura, None.