[en] Cisplatin-based chemotherapy remains frequently used to treat a wide range of solid tumors, but intrinsic and acquired resistance too often limit the success of the treatment. DNA damage-related alternative splicing (AS) profoundly affects the transcriptome. Given AS involvement in cisplatin-induced cellular responses, identify key regulators in cisplatin-induced AS could lead to new target therapeutic approaches. In this work, we used the exclusion of exons 4-5 of COASY, a robust event detected in cisplatin-treated cells, as reporter. An siRNA screening targeting 56 RNA binding proteins identified RBM39 as a positive regulator of this event in non-treated cells. Following cisplatin treatment, RBM39 depletion enhances exons 4-5 skipping, while c-JUN (known to bind to RBM39) depletion reduced it. We observed by immunoprecipitation and gPCA that the interaction between c-JUN and RBM39 was cisplatin-dependent and RNA-/DNA-independent. Importantly, c-JUN TAD phosphorylation, essential for AP-1 transcriptional activity, was not required to control spliceosome specificity. These observations, combined with the reduced recruitment of RBM39 on COASY transcripts in cisplatin-treated cells, led us to hypothesize a moonlighting role of c-JUN, where it controls the spliceosome specificity independently of its transcriptional potential via direct binding to RBM39. Transcriptome analysis in MCF7 cells depleted in c-Jun or RBM39, treated or not by cisplatin, identified hundreds of skipped exons induced by cisplatin in control cells dependent of RBM39. Among these events 80% were reduced when c-JUN was downregulated suggesting a large-scale regulation mechanism of the spliceosome by these proteins. Functionally, COASYΔE4-5 downregulation modifies the mitochondrial ultrastructure.
Research Center/Unit :
GIGA‐R - Giga‐Research - ULiège
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Lemaitre, Florence ; Université de Liège - ULiège > GIGA Molecul. Biolog. of Diseases - Gene Expression & Cancer
Chakrama, Fatima
Dequiedt, Franck ; Université de Liège - ULiège > Département des sciences de la vie > Génétique et biologie moléculaires animales
Chabot, Benoit
Klinck, R
Colige, Alain ; Université de Liège - ULiège > GIGA Cancer - Connective Tissue Biology
Piette, Jacques
Lambert, Charles
Habraken, Yvette ; Université de Liège - ULiège > GIGA Molecul. Biolog. of Diseases - Gene Expression & Cancer
Language :
English
Title :
c-Jun and RBM39 co-regulate alternative splicing induced by chemotherapy compounds
Alternative titles :
[fr] c-Jun et RBM39 co-régulent l'épissage alternatif induit par les composés chimiothérapeutiques
Publication date :
15 April 2021
Event name :
Joint Course on Post-Transcriptional Gene Regulation and Genome Instability
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