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, 2021 04 06.
Article
in En
| MEDLINE
| ID: mdl-33660780
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Introns
/
Exons
/
Spliceosomes
/
Alternative Splicing
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
Nucleic Acids Res
Year:
2021
Type:
Article
Affiliation country:
United States