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

Shaliny Ramachandran; Tiffany S Ma; Jon Griffin; Natalie Ng; Iosifina P Foskolou; Ming-Shih Hwang; Pedro Victori; Wei-Chen Cheng; Francesca M Buffa; Katarzyna B Leszczynska; Sherif F El-Khamisy; Natalia Gromak; Ester M Hammond

doi:10.1038/s41467-021-24066-z

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

Nat Commun. 2021 Jun 17;12(1):3686. doi: 10.1038/s41467-021-24066-z.

Authors

Affiliations

¹ Department of Oncology, Oxford Institute for Radiation Oncology, University of Oxford, Oxford, UK.
² Department of Molecular Biology and Biotechnology, Healthy Lifespan and Neuroscience Institute, Firth Court, University of Sheffield, Sheffield, UK.
³ Department of Histopathology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.
⁴ Laboratory of Molecular Neurobiology, Neurobiology Center, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland.
⁵ Institute of Cancer Therapeutics, University of Bradford, Bradford, UK.
⁶ Sir William Dunn School of Pathology, University of Oxford, Oxford, UK.
⁷ Department of Oncology, Oxford Institute for Radiation Oncology, University of Oxford, Oxford, UK. [email protected].

^# Contributed equally.

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

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
DNA Damage / genetics*
DNA Helicases / genetics
DNA Helicases / metabolism*
Gene Expression Regulation / drug effects
Gene Expression Regulation / genetics*
Humans
Multifunctional Enzymes / genetics
Multifunctional Enzymes / metabolism*
Nucleic Acid Synthesis Inhibitors / pharmacology
Oxygen / pharmacology
R-Loop Structures / drug effects
R-Loop Structures / genetics*
RNA Helicases / genetics
RNA Helicases / metabolism*
RNA-Seq
Unfolded Protein Response / drug effects
Unfolded Protein Response / genetics*
Up-Regulation
Zinostatin / pharmacology
eIF-2 Kinase / metabolism

Substances

ATF4 protein, human
Multifunctional Enzymes
Nucleic Acid Synthesis Inhibitors
Activating Transcription Factor 4
Zinostatin
EIF2AK3 protein, human
eIF-2 Kinase
SETX protein, human
DNA Helicases
RNA Helicases
Oxygen

Abstract

Publication types

MeSH terms

Substances

Grants and funding