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1.
Development ; 148(20)2021 10 15.
Article in English | MEDLINE | ID: mdl-34557915

ABSTRACT

Minor spliceosome inhibition due to mutations in RNU4ATAC are linked to primary microcephaly. Ablation of Rnu11, which encodes a minor spliceosome snRNA, inhibits the minor spliceosome in the developing mouse pallium, causing microcephaly. There, cell cycle defects and p53-mediated apoptosis in response to DNA damage resulted in loss of radial glial cells (RGCs), underpinning microcephaly. Here, we ablated Trp53 to block cell death in Rnu11 cKO mice. We report that Trp53 ablation failed to prevent microcephaly in these double knockout (dKO) mice. We show that the transcriptome of the dKO pallium was more similar to the control compared with the Rnu11 cKO. We find aberrant minor intron splicing in minor intron-containing genes involved in cell cycle regulation, resulting in more severely impaired mitotic progression and cell cycle lengthening of RGCs in the dKO that was detected earlier than in the Rnu11 cKO. Furthermore, we discover a potential role of p53 in causing DNA damage in the developing pallium, as detection of γH2aX+ was delayed in the dKO. Thus, we postulate that microcephaly in minor spliceosome-related diseases is primarily caused by cell cycle defects.


Subject(s)
Introns/genetics , Microcephaly/genetics , RNA Splicing/genetics , Tumor Suppressor Protein p53/genetics , Animals , Cell Cycle/genetics , Cell Death/genetics , Ependymoglial Cells/pathology , Female , Male , Mice , Mice, Knockout , Mutation/genetics , RNA, Small Nuclear/genetics , Spliceosomes/genetics , Transcriptome/genetics
2.
Nucleic Acids Res ; 49(6): 3524-3545, 2021 04 06.
Article in English | 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.


Subject(s)
Alternative Splicing , Exons , Introns , Spliceosomes/metabolism , Animals , Apoptosis Regulatory Proteins/metabolism , Cardiomyopathies/genetics , Cells, Cultured , Cerebellar Ataxia/genetics , Growth Disorders/genetics , Humans , Intellectual Disability/genetics , Mental Retardation, X-Linked/genetics , Mice , Microcephaly/genetics , Nonsense Mediated mRNA Decay , Osteochondrodysplasias/genetics , Polyribosomes/metabolism , Primary Immunodeficiency Diseases/genetics , RNA, Small Nuclear/antagonists & inhibitors , Retinal Diseases/genetics , Transcription Factors/metabolism
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