| First Author | Olthof AM | Year | 2021 |
| Journal | Nucleic Acids Res | Volume | 49 |
| Issue | 6 | Pages | 3524-3545 |
| PubMed ID | 33660780 | Mgi Jnum | J:304858 |
| Mgi Id | MGI:6693579 | Doi | 10.1093/nar/gkab118 |
| Citation | Olthof AM, et al. (2021) Disruption of exon-bridging interactions between the minor and major spliceosomes results in alternative splicing around minor introns. Nucleic Acids Res 49(6):3524-3545 |
| abstractText | 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. |
