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The X-linked trichothiodystrophy-causing gene RNF113A links the spliceosome to cell survival upon DNA damage

Author

Listed:
  • Kateryna Shostak

    (University of Liege, CHU, Sart-Tilman
    University of Liege, CHU, Sart-Tilman)

  • Zheshen Jiang

    (University of Liege, CHU, Sart-Tilman
    University of Liege, CHU, Sart-Tilman)

  • Benoit Charloteaux

    (University of Liege, CHU, Sart-Tilman
    University of Liege, CHU, Sart-Tilman
    University of Liege, Sart-Tilman)

  • Alice Mayer

    (University of Liege, CHU, Sart-Tilman
    University of Liege, CHU, Sart-Tilman)

  • Yvette Habraken

    (University of Liege, CHU, Sart-Tilman
    University of Liege, CHU, Sart-Tilman)

  • Lars Tharun

    (Institute for Pathology-University Hospital)

  • Sebastian Klein

    (Institute for Pathology-University Hospital)

  • Xinyi Xu

    (University of Liege, CHU, Sart-Tilman
    University of Liege, CHU, Sart-Tilman)

  • Hong Quan Duong

    (University of Liege, CHU, Sart-Tilman
    University of Liege, CHU, Sart-Tilman
    Duy Tan University, 03 Quang Trung)

  • Andrii Vislovukh

    (University of Liege, CHU, Sart-Tilman
    University of Liege, CHU, Sart-Tilman)

  • Pierre Close

    (University of Liege, CHU, Sart-Tilman
    University of Liege, CHU, Sart-Tilman
    Walloon Excellence in Life Sciences and Biotechnology (WELBIO))

  • Alexandra Florin

    (Institute for Pathology-University Hospital)

  • Florian Rambow

    (VIB Center for Cancer Biology and KULeuven, Department of Oncology)

  • Jean-Christophe Marine

    (VIB Center for Cancer Biology and KULeuven, Department of Oncology)

  • Reinhard Büttner

    (Institute for Pathology-University Hospital)

  • Alain Chariot

    (University of Liege, CHU, Sart-Tilman
    University of Liege, CHU, Sart-Tilman
    Walloon Excellence in Life Sciences and Biotechnology (WELBIO))

Abstract

Prolonged cell survival occurs through the expression of specific protein isoforms generated by alternate splicing of mRNA precursors in cancer cells. How alternate splicing regulates tumor development and resistance to targeted therapies in cancer remain poorly understood. Here we show that RNF113A, whose loss-of-function causes the X-linked trichothiodystrophy, is overexpressed in lung cancer and protects from Cisplatin-dependent cell death. RNF113A is a RNA-binding protein which regulates the splicing of multiple candidates involved in cell survival. RNF113A deficiency triggers cell death upon DNA damage through multiple mechanisms, including apoptosis via the destabilization of the prosurvival protein MCL-1, ferroptosis due to enhanced SAT1 expression, and increased production of ROS due to altered Noxa1 expression. RNF113A deficiency circumvents the resistance to Cisplatin and to BCL-2 inhibitors through the destabilization of MCL-1, which thus defines spliceosome inhibitors as a therapeutic approach to treat tumors showing acquired resistance to specific drugs due to MCL-1 stabilization.

Suggested Citation

  • Kateryna Shostak & Zheshen Jiang & Benoit Charloteaux & Alice Mayer & Yvette Habraken & Lars Tharun & Sebastian Klein & Xinyi Xu & Hong Quan Duong & Andrii Vislovukh & Pierre Close & Alexandra Florin , 2020. "The X-linked trichothiodystrophy-causing gene RNF113A links the spliceosome to cell survival upon DNA damage," Nature Communications, Nature, vol. 11(1), pages 1-21, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-15003-7
    DOI: 10.1038/s41467-020-15003-7
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    Cited by:

    1. Victoria O. Shender & Ksenia S. Anufrieva & Polina V. Shnaider & Georgij P. Arapidi & Marat S. Pavlyukov & Olga M. Ivanova & Irina K. Malyants & Grigory A. Stepanov & Evgenii Zhuravlev & Rustam H. Zig, 2024. "Therapy-induced secretion of spliceosomal components mediates pro-survival crosstalk between ovarian cancer cells," Nature Communications, Nature, vol. 15(1), pages 1-26, December.

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