Abstract
The advance of experimental and computational techniques has allowed us to highlight the existence of numerous different mechanisms of RNA maturation, which have been so far unknown. Besides canonical splicing, consisting of the removal of introns from pre-mRNA molecules, non-canonical splicing events may occur to further increase the regulatory and coding potential of the human genome. Among these, splicing of microexons, recursive splicing and biogenesis of circular and chimeric RNAs through back-splicing and trans-splicing processes, respectively, all contribute to expanding the repertoire of RNA transcripts with newly acquired regulatory functions. Interestingly, these non-canonical splicing events seem to occur more frequently in the central nervous system, affecting neuronal development and differentiation programs with important implications on brain physiology. Coherently, dysregulation of non-canonical RNA processing events is associated with brain disorders, including brain tumours. Herein, we summarize the current knowledge on molecular and regulatory mechanisms underlying canonical and non-canonical splicing events with particular emphasis on cis-acting elements and trans-acting factors that all together orchestrate splicing catalysis reactions and decisions. Lastly, we review the impact of non-canonical splicing on brain physiology and pathology and how unconventional splicing mechanisms may be targeted or exploited for novel therapeutic strategies in cancer.
Highlights
Almost all human genes are transcribed and spliced in order to generate mature transcripts before being translated into proteins or to carry out specific regulatory functions as non-coding RNAs [1]
Competition between splice sites, differential recruitment of splicing factors and/or RNA-binding proteins (RBPs), DNA and RNA modifications, chromatin and RNA secondary structures, kinetics of transcriptional elongation and intron removal, all contribute to regulation of splicing, greatly expanding the number of transcript variants arising from a single gene locus through a process termed alternative splicing [3]
Unlike canonical pre-messenger RNA (mRNA) splicing, in which the 50 splice site of an upstream exon is joined with the 30 splice site of a downstream exon, back-splicing is an event in which the 50 splice site of a downstream exon is joined with the 30 splice site of an upstream exon, yielding a circular transcript [29]
Summary
Almost all human genes are transcribed and spliced in order to generate mature transcripts before being translated into proteins or to carry out specific regulatory functions as non-coding RNAs [1]. Competition between splice sites, differential recruitment of splicing factors and/or RNA-binding proteins (RBPs), DNA and RNA modifications, chromatin and RNA secondary structures, kinetics of transcriptional elongation and intron removal, all contribute to regulation of splicing, greatly expanding the number of transcript variants arising from a single gene locus through a process termed alternative splicing [3]. These regulatory mechanisms greatly impact splicing efficiency, contributing, at least in part, to unconventional splicing events that can occur alternatively or concomitantly with canonical splicing events (see below). We discuss the molecular mechanisms underlying canonical and non-canonical splicing events, with particular emphasis on the impact of unconventional splicing events on brain physiology and pathology
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