Disruption of exon-bridging interactions between the minor and major spliceosomes results in alternative splicing around minor introns
- Olthof, AM; White, AK; Mieruszynski, S; Doggett, K; Lee, MF; Chakroun, A; Abdel Aleem, AK; Rousseau, J; Magnani, C; Roifman, CM; Campeau, PM; Heath, JK; Kanadia, RN;
Publication Year 2021-02-28, Volume 49, Issue #6, Page 3524-2545
- Journal Title
- Nucleic Acids Research
- 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.
- Oxford Academic
- WEHI Research Division(s)
- Epigenetics And Development
- PubMed ID
- Publisher's Version
- Open Access at Publisher's Site
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Creation Date: 2021-05-13 09:20:20Last Modified: 2021-05-13 11:00:08