Hypoxia-induced SETX links replication stress with the unfolded protein response

• Published in: Nature communications Vol. 12; no. 1; pp. 3686 - 14
• Main Authors: Ramachandran, Shaliny, Ma, Tiffany S., Griffin, Jon, Ng, Natalie, Foskolou, Iosifina P., Hwang, Ming-Shih, Victori, Pedro, Cheng, Wei-Chen, Buffa, Francesca M., Leszczynska, Katarzyna B., El-Khamisy, Sherif F., Gromak, Natalia, Hammond, Ester M.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 17.06.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/106; 13/51; 49/109; 49/88; 49/90; 49/91; 631/337; 631/67; 631/80; 82/29; 82/80; 96/63; Activating Transcription Factor 4 - genetics; Activating Transcription Factor 4 - metabolism; Cell Death - drug effects; Cell Death - genetics; Cell Hypoxia; Cell Line, Tumor; Cell Survival - drug effects; Cell Survival - genetics; Chromatin Immunoprecipitation; Damage accumulation; Deoxyribonucleic acid; DNA; DNA biosynthesis; DNA damage; DNA Damage - genetics; DNA helicase; DNA Helicases - genetics; DNA Helicases - metabolism; eIF-2 Kinase - metabolism; Gene Expression Regulation - drug effects; Gene Expression Regulation - genetics; Humanities and Social Sciences; Humans; Hypoxia; Mammalian cells; multidisciplinary; Multifunctional Enzymes - genetics; Multifunctional Enzymes - metabolism; Nucleic Acid Synthesis Inhibitors - pharmacology; Oxygen - pharmacology; Protein folding; Proteins; R-Loop Structures - drug effects; R-Loop Structures - genetics; R-loops; Replication; Ribonucleic acid; RNA; RNA helicase; RNA Helicases - genetics; RNA Helicases - metabolism; RNA-Seq; Science; Science (multidisciplinary); Transcription activation; Transcription factors; Tumors; Unfolded Protein Response - drug effects; Unfolded Protein Response - genetics; Up-Regulation; Zinostatin - pharmacology
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-24066-z

Tumour hypoxia is associated with poor patient prognosis and therapy resistance. A unique transcriptional response is initiated by hypoxia which includes the rapid activation of numerous transcription factors in a background of reduced global transcription. Here, we show that the biological response to hypoxia includes the accumulation of R-loops and the induction of the RNA/DNA helicase SETX. In the absence of hypoxia-induced SETX, R-loop levels increase, DNA damage accumulates, and DNA replication rates decrease. Therefore, suggesting that, SETX plays a role in protecting cells from DNA damage induced during transcription in hypoxia. Importantly, we propose that the mechanism of SETX induction in hypoxia is reliant on the PERK/ATF4 arm of the unfolded protein response. These data not only highlight the unique cellular response to hypoxia, which includes both a replication stress-dependent DNA damage response and an unfolded protein response but uncover a novel link between these two distinct pathways. Hypoxia induces a change in transcriptional response in mammalian cells. Here the authors reveal a role for the RNA/DNA helicase Senataxin in protecting cells from DNA damage induced during transcription in hypoxia.