Abstract 2807: Determining a role for a long noncoding RNA involved in the DNA damage response of lung adenocarcinoma

Abstract Lung adenocarcinoma (LUAD) is the most common histological subtype of the deadliest cancer in the United States. This cancer accounts for 40% of cases that can arise from a high rate of mutations that is exaggerated by dysregulation in the DNA damage and repair signaling pathways that cause genomic instability. Historically, the role of protein coding genes in regulation of these pathways has been extensively studied but developments in new technology has identified noncoding RNAs as critical regulators involved in physiological and pathological processes related to DNA stability. Specifically, long noncoding RNAs (lncRNAs) have been implicated as critical regulators of gene expression in the DNA damage response; controlling the repair mechanism response's magnitude, duration, and resolution, but very few have been characterized and ascribed a function. We have previously identified the lncRNA, LINC00261, that acts as a tumor suppressor in LUAD by regulating the activation of the DNA damage repair system. However, its exact mechanisms of action in the signaling pathway remain unknown. We found that reintroduction of LINC00261 in LUAD is associated with G2/M cell cycle arrest and phosphorylation-mediated activation of key DNA damage response pathway components. We hypothesize that LINC00261 maintains DNA fidelity through direct interaction with repair components. To gain critical insights into the essential functions that LINC00261 plays in the DNA damage response, a mediation analysis including LINC00261 and tumor mutational burden was conducted on the TCGA LUAD dataset. Results of this mediation analysis suggested a role for LINC00261 in nucleotide excision repair (NER) pathway in lung adenocarcinoma. To mechanistically characterize the function of LINC00261 in NER, we have conducted ChIRP-MS in the A549 LUAD cell line. Our preliminary results indicate LINC00261 direct interaction with mitochondrial translation (p=1.34E-13), rRNA processing in the nucleolus and cytosol (p=3.76E-10), and branched-chain amino acid catabolism, (p=5.68E-09) pathways. Further validation of the relationship between LINC00261 and NER was performed on RNA isolated from A549 cells upon UVC DNA damage. LINC00261 was subcellularly localized to both cytoplasm and nucleus, inferring that LINC00261 can function in cis and trans. We are currently investigating LINC00261 direct binding partners that mediate DNA damage and repair responses. Our findings provide evidence for the role of LINC00261 in the DNA damage response and will lead to a further understanding of how lncRNA-mediated dysregulation of DNA repair leads to genomic instability and oncogenic activation. Citation Format: Michele Ramos Correa, Jonathan Castillo, Patrick Pirrotte, Crystal N. Marconett. Determining a role for a long noncoding RNA involved in the DNA damage response of lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2807.