Disruption of exon-bridging interactions between the minor and major spliceosomes results in alternative splicing around minor introns
Details
Publication Year 2021-02-28, Volume 49, Issue #6, Page 3524-2545
Journal Title
Nucleic Acids Research
Abstract
Vertebrate genomes contain major (>99.5%) and minor (<0.5%) introns that are spliced by the major and minor spliceosomes, respectively. Major intron splicing follows the exon-definition model, whereby major spliceosome components first assemble across exons. However, since most genes with minor introns predominately consist of major introns, formation of exon-definition complexes in these genes would require interaction between the major and minor spliceosomes. Here, we report that minor spliceosome protein U11-59K binds to the major spliceosome U2AF complex, thereby supporting a model in which the minor spliceosome interacts with the major spliceosome across an exon to regulate the splicing of minor introns. Inhibition of minor spliceosome snRNAs and U11-59K disrupted exon-bridging interactions, leading to exon skipping by the major spliceosome. The resulting aberrant isoforms contained a premature stop codon, yet were not subjected to nonsense-mediated decay, but rather bound to polysomes. Importantly, we detected elevated levels of these alternatively spliced transcripts in individuals with minor spliceosome-related diseases such as Roifman syndrome, Lowry-Wood syndrome and early-onset cerebellar ataxia. In all, we report that the minor spliceosome informs splicing by the major spliceosome through exon-definition interactions and show that minor spliceosome inhibition results in aberrant alternative splicing in disease.
Publisher
Oxford Academic
WEHI Research Division(s)
Epigenetics And Development
PubMed ID
33660780
Open Access at Publisher's Site
https://doi.org/10.1093/nar/gkab118
Rights Notice
Refer to copyright notice on published article.


Creation Date: 2021-05-13 09:20:20
Last Modified: 2021-05-13 11:00:08
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