Cancer associated SF3B1 mutants recognize otherwise inaccessible cryptic 3’ splice sites within RNA secondary structures
| Autor: | Oscar Ramirez, Tushar Murthy, Alex C. Minella, Xiaodong Yang, Manoj M. Pillai, Abhishek K. Gupta, Anil K. Kesarwani |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
RNA Splicing Factors Cancer Research Spliceosome RNA Splicing Exonic splicing enhancer Prp24 Biology medicine.disease_cause Article 03 medical and health sciences Gene expression Genetics medicine Tumor Cells Cultured Humans RNA Neoplasm Molecular Biology MYELODYSPLASTIC SYNDROME Mutation SF3B1 RNA Phosphoproteins CANCER Leukemia Lymphocytic Chronic B-Cell 3. Good health 030104 developmental biology Myelodysplastic Syndromes RNA splicing Spliceosomes Nucleic Acid Conformation RNA Splice Sites SPLICING Transcriptome |
| Zdroj: | Oncogene |
| ISSN: | 1476-5594 0950-9232 |
| Popis: | Recurrent mutations in core splicing factors have been reported in several clonal disorders, including cancers. Mutations in SF3B1, a component of the U2 splicing complex, are the most common. SF3B1 mutations are associated with aberrant pre-mRNA splicing using cryptic 3' splice sites (3'SSs), but the mechanism of their selection is not clear. To understand how cryptic 3'SSs are selected, we performed comprehensive analysis of transcriptome-wide changes to splicing and gene expression associated with SF3B1 mutations in patient samples as well as an experimental model of inducible expression. Hundreds of cryptic 3'SS were detectable across the genome in cells expressing mutant SF3B1. These 3'SS are typically sequestered within RNA secondary structures and poorly accessible compared with their corresponding canonical 3'SS. We hypothesized that these cryptic 3'SS are inaccessible during normal splicing catalysis and that this constraint is overcome in spliceosomes containing mutant SF3B1. This model of secondary structure-dependent selection of cryptic 3'SS was found across multiple clonal processes associated with SF3B1 mutations (myelodysplastic syndrome and chronic lymphocytic leukemia). We validated our model predictions in mini-gene splicing assays. Additionally, we found deregulated expression of proteins with relevant functions in splicing factor-related diseases both in association with aberrant splicing and without corresponding splicing changes. Our results show that SF3B1 mutations are associated with a distinct splicing program shared across multiple clonal processes and define a biochemical mechanism for altered 3'SS choice. |
| Databáze: | OpenAIRE |
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