SRSF2 Mutations Contribute to Myelodysplasia by Mutant-Specific Effects on Exon Recognition
| Autor: | Frédéric H.-T. Allain, Eunhee Kim, Silvia Buonamici, Aravind Ramakrishnan, Jean Baptiste Micol, Ahmad S. Zebari, Young Rock Chung, Omar Abdel-Wahab, H. Joachim Deeg, Robert K. Bradley, Pete Smith, Stanley Chun-Wei Lee, Iannis Aifantis, Yorgo Modis, Michele E. Murphy, Yang Liang, Camille Lobry, Janine O. Ilagan, Shlomzion Aumann, Min Kyung Kim, Yue Li, Gerrit M. Daubner, Christopher Y. Park, Hana Cho, Stephanie Halene |
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| Přispěvatelé: | Modis, Yorgo [0000-0002-6084-0429], Apollo - University of Cambridge Repository |
| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Cancer Research
RNA Splicing Mutant Exonic splicing enhancer Gene Expression Biology medicine.disease_cause Article 03 medical and health sciences Exon Splicing factor Mice 0302 clinical medicine medicine Animals Enhancer of Zeste Homolog 2 Protein Loss function health care economics and organizations 030304 developmental biology Genetics 0303 health sciences Mutation Serine-Arginine Splicing Factors EZH2 Polycomb Repressive Complex 2 Nuclear Proteins Cell Biology Exons Mice Mutant Strains 3. Good health Oncology Ribonucleoproteins 030220 oncology & carcinogenesis Myelodysplastic Syndromes RNA splicing Proteolysis |
| Popis: | SummaryMutations affecting spliceosomal proteins are the most common mutations in patients with myelodysplastic syndromes (MDS), but their role in MDS pathogenesis has not been delineated. Here we report that mutations affecting the splicing factor SRSF2 directly impair hematopoietic differentiation in vivo, which is not due to SRSF2 loss of function. By contrast, SRSF2 mutations alter SRSF2’s normal sequence-specific RNA binding activity, thereby altering the recognition of specific exonic splicing enhancer motifs to drive recurrent mis-splicing of key hematopoietic regulators. This includes SRSF2 mutation-dependent splicing of EZH2, which triggers nonsense-mediated decay, which, in turn, results in impaired hematopoietic differentiation. These data provide a mechanistic link between a mutant spliceosomal protein, alterations in the splicing of key regulators, and impaired hematopoiesis. |
| Databáze: | OpenAIRE |
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