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

Luisa Statello; Mohamad M Ali; Silke Reischl; Sagar Mahale; Subazini Thankaswamy Kosalai; Maite Huarte; Chandrasekhar Kanduri

doi:10.1093/narcan/zcab002

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

NAR Cancer. 2021 Feb 1;3(1):zcab002. doi: 10.1093/narcan/zcab002. eCollection 2021 Mar.

Authors

Luisa Statello¹, Mohamad M Ali¹, Silke Reischl¹, Sagar Mahale¹, Subazini Thankaswamy Kosalai¹, Maite Huarte², Chandrasekhar Kanduri¹

Affiliations

¹ Department of Medical Biochemistry and Cell Biology, The Sahlgrenska Academy, Institute of Biomedicine, University of Gothenburg, SE-40530 Gothenburg, Sweden.
² Department of Gene Therapy and Regulation of Gene Expression, Center for Applied Medical Research, University of Navarra, Pamplona 31008, Spain.

Abstract

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.