Abstract 6002: The lncRNA TUG1 enhances helicase-mediated R-loop resolution through RNA-protein interaction

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. Citation Format: Shuya Mimura, Jingqi Xie, Miho M. Suzuki, Yutaka Kondo. The lncRNA TUG1 enhances helicase-mediated R-loop resolution through RNA-protein interaction [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6002.