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

Nature Communications
Kateryna ShostakAlain Chariot

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.

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Citations

Jan 13, 2021·Critical Reviews in Biochemistry and Molecular Biology·Ning TsaoNima Mosammaparast
Dec 4, 2020·Cell Research·Daolin TangGuido Kroemer
Apr 4, 2021·Cells·Sanna Abbasi, Caroline Schild-Poulter
Apr 29, 2021·Human Molecular Genetics·Elena BottaWim Vermeulen
May 18, 2021·Frontiers in Molecular Biosciences·Sonia JimenoPablo Huertas
Aug 8, 2021·Cancers·Can HuangJuan Iovanna

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Datasets Mentioned

BETA
ABT737

Methods Mentioned

BETA
PCR
ChIP
FACS
Assay
immunoprecipitation
immunoprecipitations
RNAseq
RNA-Seq
PCRs
transfections

Software Mentioned

SeqNLS
HTseq
OpenComet
rMATS (
replicate Multivariate Analysis of Transcript Splicing )
STAR
R Foundation for Statistical Computing
FlowJo
MultiQC
Ensembl

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