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.

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