The X-linked trichothiodystrophy-causing gene RNF113A links the spliceosome to cell survival upon DNA damage.
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.
Mesh Terms:
A549 Cells, Adenocarcinoma of Lung, Alternative Splicing, Animals, Basic Helix-Loop-Helix Transcription Factors, Cell Nucleus, Cell Survival, Cisplatin, Cytoprotection, DNA Damage, DNA-Activated Protein Kinase, DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, Genes, X-Linked, Humans, Introns, Mice, Inbred NOD, Mice, SCID, Myeloid Cell Leukemia Sequence 1 Protein, Neoplasm Proteins, Phosphorylation, Protein Stability, Protein Subunits, Proto-Oncogene Proteins c-bcl-2, RNA, Messenger, Reactive Oxygen Species, Spliceosomes, Trichothiodystrophy Syndromes
A549 Cells, Adenocarcinoma of Lung, Alternative Splicing, Animals, Basic Helix-Loop-Helix Transcription Factors, Cell Nucleus, Cell Survival, Cisplatin, Cytoprotection, DNA Damage, DNA-Activated Protein Kinase, DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, Genes, X-Linked, Humans, Introns, Mice, Inbred NOD, Mice, SCID, Myeloid Cell Leukemia Sequence 1 Protein, Neoplasm Proteins, Phosphorylation, Protein Stability, Protein Subunits, Proto-Oncogene Proteins c-bcl-2, RNA, Messenger, Reactive Oxygen Species, Spliceosomes, Trichothiodystrophy Syndromes
Nat Commun
Date: Dec. 09, 2019
PubMed ID: 32152280
View in: Pubmed Google Scholar
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