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

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...

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Veröffentlicht in:	Nature communications Jg. 12; H. 1; S. 3686 - 14
Hauptverfasser:	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
Sprache:	Englisch
Veröffentlicht:	London Nature Publishing Group UK 17.06.2021 Nature Publishing Group Nature Portfolio
Schlagworte:	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
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Zusammenfassung:	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.
Bibliographie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-021-24066-z