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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Bibliographic Details
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:
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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
Online Access:Get full text
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Summary: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.
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ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-021-24066-z