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

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, Florian Rambow, Jean-Christophe Marine, Reinhard Büttner and Alain Chariot ()
Additional contact information
Kateryna Shostak: University of Liege, CHU, Sart-Tilman
Zheshen Jiang: University of Liege, CHU, Sart-Tilman
Benoit Charloteaux: University of Liege, CHU, Sart-Tilman
Alice Mayer: University of Liege, CHU, Sart-Tilman
Yvette Habraken: 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
Hong Quan Duong: University of Liege, CHU, Sart-Tilman
Andrii Vislovukh: University of Liege, CHU, Sart-Tilman
Pierre Close: University of Liege, CHU, Sart-Tilman
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

Nature Communications, 2020, vol. 11, issue 1, 1-21

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-15003-7

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