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

Kateryna Shostak1,2, Zheshen Jiang1,2, Benoit Charloteaux1,3,4

  • 1Interdisciplinary Cluster for Applied Genoproteomics (GIGA), University of Liege, CHU, Sart-Tilman, Liège, Belgium.

Nature Communications
|March 11, 2020
PubMed

Insights

RNF113A overexpression in lung cancer promotes cell survival by regulating RNA splicing. Its deficiency triggers cancer cell death via apoptosis and ferroptosis, offering new therapeutic strategies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Alternate RNA splicing generates protein isoforms crucial for cancer cell survival.
  • The role of alternate splicing in tumor development and therapy resistance is not fully understood.
  • RNF113A, linked to X-linked trichothiodystrophy, is implicated in cancer biology.

Purpose of the Study:

  • To investigate the role of RNF113A in lung cancer.
  • To determine how RNF113A influences cancer cell survival and response to therapy.
  • To explore RNF113A's impact on RNA splicing and downstream cellular pathways.

Main Methods:

  • Analysis of RNF113A expression in lung cancer.
  • Investigating RNF113A's function as an RNA-binding protein.
  • Assessing cell death mechanisms (apoptosis, ferroptosis) upon RNF113A deficiency.
  • Evaluating RNF113A's effect on MCL-1, SAT1, and Noxa1 expression and splicing.

Main Results:

  • RNF113A is overexpressed in lung cancer and confers resistance to Cisplatin.
  • RNF113A regulates splicing of multiple genes involved in cell survival.
  • RNF113A deficiency induces apoptosis (via MCL-1 destabilization), ferroptosis (via SAT1 upregulation), and ROS production (via Noxa1 alteration).
  • RNF113A deficiency overcomes resistance to Cisplatin and BCL-2 inhibitors by destabilizing MCL-1.

Conclusions:

  • RNF113A plays a significant role in lung cancer cell survival and chemoresistance.
  • Targeting RNF113A or its downstream pathways could be a therapeutic strategy.
  • Spliceosome inhibitors represent a promising approach for treating drug-resistant cancers with MCL-1 stabilization.

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