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Recursive splicing in long vertebrate genes
#MMPMID25970246
Sibley CR
; Emmett W
; Blazquez L
; Faro A
; Haberman N
; Briese M
; Trabzuni D
; Ryten M
; Weale ME
; Hardy J
; Modic M
; Curk T
; Wilson SW
; Plagnol V
; Ule J
Nature
2015[May]; 521
(7552
): 371-375
PMID25970246
show ga
It is generally believed that splicing removes introns as single units from
precursor messenger RNA transcripts. However, some long Drosophila melanogaster
introns contain a cryptic site, known as a recursive splice site (RS-site), that
enables a multi-step process of intron removal termed recursive splicing. The
extent to which recursive splicing occurs in other species and its mechanistic
basis have not been examined. Here we identify highly conserved RS-sites in genes
expressed in the mammalian brain that encode proteins functioning in neuronal
development. Moreover, the RS-sites are found in some of the longest introns
across vertebrates. We find that vertebrate recursive splicing requires initial
definition of an 'RS-exon' that follows the RS-site. The RS-exon is then excluded
from the dominant mRNA isoform owing to competition with a reconstituted 5'
splice site formed at the RS-site after the first splicing step. Conversely, the
RS-exon is included when preceded by cryptic promoters or exons that fail to
reconstitute an efficient 5' splice site. Most RS-exons contain a premature stop
codon such that their inclusion can decrease mRNA stability. Thus, by
establishing a binary splicing switch, RS-sites demarcate different mRNA isoforms
emerging from long genes by coupling cryptic elements with inclusion of RS-exons.
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