The DNA damage inducible lncRNA SCAT7 regulates genomic integrity and topoisomerase 1 turnover in lung adenocarcinoma

• Published in: NAR cancer 2021-03, Vol.3 (1), p.zcab002-zcab002
• Main Authors: Statello, Luisa, Ali, Mohamad M, Reischl, Silke, Mahale, Sagar, Kosalai, Subazini Thankaswamy, Huarte, Maite, Kanduri, Chandrasekhar
• Format: Article
• Language: English
• Subjects: Biochemistry and Molecular Biology; Biokemi och molekylärbiologi; DNA Damage Sensing and Repair
• ISSN: 2632-8674; 2632-8674
• DOI: 10.1093/narcan/zcab002

Despite the rapid improvements in unveiling the importance of lncRNAs in all aspects of cancer biology, there is still a void in mechanistic understanding of their role in the DNA damage response. Here we explored the potential role of the oncogenic lncRNA SCAT7 (ELF3-AS1) in the maintenance of genome integrity. We show that SCAT7 is upregulated in response to DNA-damaging drugs like cisplatin and camptothecin, where SCAT7 expression is required to promote cell survival. SCAT7 silencing leads to decreased proliferation of cisplatin-resistant cells in vitro and in vivo through interfering with cell cycle checkpoints and DNA repair molecular pathways. SCAT7 regulates ATR signaling, promoting homologous recombination. Importantly, SCAT7 also takes part in proteasome-mediated topoisomerase I (TOP1) degradation, and its depletion causes an accumulation of TOP1–cc structures responsible for the high levels of intrinsic DNA damage. Thus, our data demonstrate that SCAT7 is an important constituent of the DNA damage response pathway and serves as a potential therapeutic target for hard-to-treat drug resistant cancers.