Prp8 impacts cryptic but not alternative splicing frequency
| Autor: | J. Matthew Ragle, Christine Guthrie, Megan Mayerle, Sol Katzman, Samira Yitiz, Lucero E Rogel, Alan M. Zahler, Cameron M. Soulette, Andrea Ramirez |
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| Rok vydání: | 2019 |
| Předmět: |
Models
Molecular Spliceosome Saccharomyces cerevisiae Proteins Ribonucleoprotein U4-U6 Small Nuclear Protein Conformation PRP8 U4-U6 Small Nuclear alternative splicing 03 medical and health sciences U5 Small Nuclear 0302 clinical medicine Gene Frequency Models RNA Precursors Genetics Animals splice Amino Acid Sequence Amino Acids Allele Caenorhabditis elegans Ribonucleoprotein U5 Small Nuclear Conserved Sequence Alleles 030304 developmental biology 0303 health sciences Multidisciplinary biology cryptic splicing Alternative splicing Molecular Ribonucleoprotein biology.organism_classification CRISPR mutagenesis Alternative Splicing MRNA Sequencing PNAS Plus Amino Acid Substitution Genetic Loci RNA splicing Spliceosomes RNA Splice Sites Generic health relevance spliceosome 030217 neurology & neurosurgery Genetic screen |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America, vol 116, iss 6 |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | Pre-mRNA splicing must occur with extremely high fidelity. Spliceosomes assemble onto pre-mRNA guided by specific sequences (5′ splice site, 3′ splice site, and branchpoint). When splice sites are mutated, as in many hereditary diseases, the spliceosome can aberrantly select nearby pseudo- or “cryptic” splice sites, often resulting in nonfunctional protein. How the spliceosome distinguishes authentic splice sites from cryptic splice sites is poorly understood. We performed a Caenorhabditis elegans genetic screen to find cellular factors that affect the frequency with which the spliceosome uses cryptic splice sites and identified two alleles in core spliceosome component Prp8 that alter cryptic splicing frequency. Subsequent complementary genetic and structural analyses in yeast implicate these alleles in the stability of the spliceosome’s catalytic core. However, despite a clear effect on cryptic splicing, high-throughput mRNA sequencing of these prp-8 mutant C. elegans reveals that overall alternative splicing patterns are relatively unchanged. Our data suggest the spliceosome evolved intrinsic mechanisms to reduce the occurrence of cryptic splicing and that these mechanisms are distinct from those that impact alternative splicing. |
| Databáze: | OpenAIRE |
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