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

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.

• Authors: 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, Alain Chariot
• Journal: Nature communications (Nat Commun) Vol. 11 Issue 1 Pg. 1270 (03 09 2020) ISSN: 2041-1723 [Electronic] England
• PMID: 32152280 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Basic Helix-Loop-Helix Transcription Factors
• DNA-Binding Proteins
• MCL1 protein, human
• Myeloid Cell Leukemia Sequence 1 Protein
• NUPR1 protein, human
• Neoplasm Proteins
• PMAIP1 protein, human
• Protein Subunits
• Proto-Oncogene Proteins c-bcl-2
• RNA, Messenger
• RNF113A protein, human
• Reactive Oxygen Species
• DNA-Activated Protein Kinase
• PRKDC protein, human
• Cisplatin

Topics

• A549 Cells
• Adenocarcinoma of Lung (genetics, pathology)
• Alternative Splicing (genetics)
• Animals
• Basic Helix-Loop-Helix Transcription Factors (metabolism)
• Cell Nucleus (drug effects, metabolism)
• Cell Survival (genetics)
• Cisplatin (pharmacology)
• Cytoprotection (drug effects)
• DNA Damage (genetics)
• DNA-Activated Protein Kinase (metabolism)
• DNA-Binding Proteins (deficiency, genetics, metabolism)
• Gene Expression Regulation, Neoplastic (drug effects)
• Genes, X-Linked
• Humans
• Introns (genetics)
• Mice, Inbred NOD
• Mice, SCID
• Myeloid Cell Leukemia Sequence 1 Protein (metabolism)
• Neoplasm Proteins (metabolism)
• Phosphorylation (drug effects)
• Protein Stability (drug effects)
• Protein Subunits (metabolism)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• RNA, Messenger (genetics, metabolism)
• Reactive Oxygen Species (metabolism)
• Spliceosomes (metabolism)
• Trichothiodystrophy Syndromes (genetics)