The exon junction complex is required for DMD gene splicing fidelity and myogenic differentiation

Cell Mol Life Sci. 2024 Mar 21;81(1):150. doi: 10.1007/s00018-024-05188-1.ABSTRACTDeposition of the exon junction complex (EJC) upstream of exon-exon junctions helps maintain transcriptome integrity by preventing spurious re-splicing events in already spliced mRNAs. Here we investigate the importance of EJC for the correct splicing of the 2.2-megabase-long human DMD pre-mRNA, which encodes dystrophin, an essential protein involved in cytoskeletal organization and cell signaling. Using targeted RNA-seq, we show that knock-down of the eIF4A3 and Y14 core components of EJC in a human muscle cell line causes an accumulation of mis-splicing events clustered towards the 3' end of the DMD transcript (Dp427m). This deregulation is conserved in the short Dp71 isoform expressed ubiquitously except in adult skeletal muscle and is rescued with wild-type eIF4A3 and Y14 proteins but not with an EJC assembly-defective mutant eIF4A3. MLN51 protein and EJC-associated ASAP/PSAP complexes independently modulate the inclusion of the regulated exons 71 and 78. Our data confirm the protective role of EJC in maintaining splicing fidelity, which in the DMD gene is necessary to preserve the function of the critical C-terminal protein-protein interaction domain of dystrophin present in all tissue-specific isoforms. Given the role of the EJC in maintaining the integrity of dystrophin, we asked whether the EJC could also be involved in the regulation of a mechanism as complex as skeletal muscle differen...

Source: Cellular and Molecular Life Sciences : CMLS - March 21, 2024 Category: Cytology Authors: Dylan Da Cunha Julie Miro Charles Van Goethem C écile Notarnicola G érald Hugon Gilles Carnac Mireille Coss ée Michel Koenig Sylvie Tuffery-Giraud Source Type: research