Abstract

SummaryRecursive 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.

Highlights

  • Alternative splicing (AS) is regulated by many proteins that bind to the nascent RNA to modulate the initial step of exon definition (Jangi and Sharp, 2014)

  • Recursive splicing (RS) starts by defining an ‘‘RSexon,’’ which is spliced to the preceding exon, creating a recursive 50 splice site (RS-5ss)

  • Previous studies focused on cryptic RS-exons, and we find that the exon junction complex (EJC) represses RS of hundreds of annotated, mainly constitutive RS-exons

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Summary

Introduction

Alternative splicing (AS) is regulated by many proteins that bind to the nascent RNA to modulate the initial step of exon definition (Jangi and Sharp, 2014). Less is known about the role of proteins binding to spliced RNA, which could regulate a two-step splicing process, such as recursive splicing (RS) (Hatton et al, 1998; Sibley et al, 2015). In the second step of RS, use of the RS-5ss leads to skipping the RS-exon along with the downstream intron. The factors that could bind to the part-spliced transcript to regulate inclusion of RS-exons remained unknown

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