Blazquez, LoreaEmmett, WarrenFaraway, RupertPineda, Jose Mario BelloBajew, Simon, 1994-Gohr, AndréHaberman, NejcSibley, Christopher R.Bradley, Robert K.Irimia Martínez, ManuelUle, Jernej2019-11-222019-11-222018Blazquez L, Emmett W, Faraway R, Pineda JMB, Bajew S, Gohr A, Haberman N, Sibley CR, Bradley RK, Irimia M, Ule J. Exon junction complex shapes the transcriptome by repressing recursive splicing. Mol Cell. 2018; 72(3):496-509.e9. DOI 10.1016/j.molcel.2018.09.0331097-2765http://hdl.handle.net/10230/42934Recursive splicing (RS) starts by defining an "RS-exon," which is then spliced to the preceding exon, thus creating a recursive 5' splice site (RS-5ss). Previous studies focused on cryptic RS-exons, and now we find that the exon junction complex (EJC) represses RS of hundreds of annotated, mainly constitutive RS-exons. The core EJC factors, and the peripheral factors PNN and RNPS1, maintain RS-exon inclusion by repressing spliceosomal assembly on RS-5ss. The EJC also blocks 5ss located near exon-exon junctions, thus repressing inclusion of cryptic microexons. The prevalence of annotated RS-exons is high in deuterostomes, while the cryptic RS-exons are more prevalent in Drosophila, where EJC appears less capable of repressing RS. Notably, incomplete repression of RS also contributes to physiological alternative splicing of several human RS-exons. Finally, haploinsufficiency of the EJC factor Magoh in mice is associated with skipping of RS-exons in the brain, with relevance to the microcephaly phenotype and human diseases.application/pdfeng© 2018 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).info:eu-repo/semantics/articlehttp://dx.doi.org/10.1016/j.molcel.2018.09.033RS exonAlternative splicing mechanismsEvolutionExon junction complexGene expressionMicrocephalyMicroexonNeurodevelopmental disordersRecursive splicinginfo:eu-repo/semantics/openAccess