c-Jun directly controls spliceosome specificity through RBM39 binding in response to genotoxic chemotherapy

Cisplatin-based treatments are often impeded by tumors resistance. Here, we identified all genes differently expressed and/or alternatively spliced by cisplatin in MCF7 cells and selected the simultaneous exclusion of exons 4 and 5 of mitochondrial Co-enzyme A Synthase as prototypical event. This undocumented inactive COASY-ΔE4-5 isoform accumulates in all cisplatin-sensitive cell lines tested. Importantly, its downregulation
by RNAi decreases mitochondrial fitness, prevents cisplatin-induced mitochondrial fusion and enhances cisplatin resistance. An siRNA screen of 56 RBPs identified RBM39 as main regulator of this specific exclusion event. Global transcriptome analysis revealed that 28% of cisplatin-induced cassette exon are RBM39-dependent. Pursuing the enquiry to decipher RBM39 regulation in stress situation, we noted that its interaction with c-Jun is greatly enhanced by cisplatin and concomitant to its reduced recruitment to COASY-pre-mRNA. Finally, transcriptomic analysis unveiled that RBM39- and cisplatin-dependent cassette exon
modifications are more affected by c-Jun downregulation than RBM39-independent events. Importantly c-Jun transcriptional potential is not involved in this control as the phosphorylation of S63 and S73 are not required and genes undergoing splicing modification are AP-1 independent. This constitutes the first report of a genome-wide direct control of the spliceosome assembly by c-Jun based on its interaction with a splicing factor.