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

Author

Listed:
  • Shaliny Ramachandran

    (University of Oxford)

  • Tiffany S. Ma

    (University of Oxford)

  • Jon Griffin

    (University of Sheffield
    Sheffield Teaching Hospitals NHS Foundation Trust)

  • Natalie Ng

    (University of Oxford)

  • Iosifina P. Foskolou

    (University of Oxford)

  • Ming-Shih Hwang

    (University of Oxford)

  • Pedro Victori

    (University of Oxford)

  • Wei-Chen Cheng

    (University of Oxford)

  • Francesca M. Buffa

    (University of Oxford)

  • Katarzyna B. Leszczynska

    (University of Oxford
    Polish Academy of Sciences)

  • Sherif F. El-Khamisy

    (University of Sheffield
    University of Bradford)

  • Natalia Gromak

    (University of Oxford)

  • Ester M. Hammond

    (University of Oxford)

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.

Suggested Citation

  • 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, 2021. "Hypoxia-induced SETX links replication stress with the unfolded protein response," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-24066-z
    DOI: 10.1038/s41467-021-24066-z
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    Cited by:

    1. Abhishek Bharadwaj Sharma & Muhammad Khairul Ramlee & Joel Kosmin & Martin R. Higgs & Amy Wolstenholme & George E. Ronson & Dylan Jones & Daniel Ebner & Noor Shamkhi & David Sims & Paul W. G. Wijnhove, 2023. "C16orf72/HAPSTR1/TAPR1 functions with BRCA1/Senataxin to modulate replication-associated R-loops and confer resistance to PARP disruption," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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