Recurrent SRSF2 mutations in MDS affect both splicing and NMD

Oncogenic mutations in the RNA splicing factors SRSF2, SF3B1, and U2AF1 are the most frequent class of mutations in myelodysplastic syndromes and are also common in clonal hematopoiesis, acute myeloid leukemia, chronic lymphocytic leukemia, and a variety of solid tumors. They cause genome-wide splic...

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Bibliographic Details
Published in:Genes & development 2020-03, Vol.34 (5-6), p.413-427
Main Authors: Rahman, Mohammad Alinoor, Lin, Kuan-Ting, Bradley, Robert K, Abdel-Wahab, Omar, Krainer, Adrian R
Format: Article
Language:English
Subjects:
Cell Line, Tumor
HeLa Cells
Humans
K562 Cells
Leukemia, Myeloid, Acute - genetics
Mutation - genetics
Myelodysplastic Syndromes - genetics
Nonsense Mediated mRNA Decay - genetics
Research Paper
RNA Splicing - genetics
RNA Stability - genetics
Serine-Arginine Splicing Factors - genetics
Serine-Arginine Splicing Factors - metabolism
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Summary:Oncogenic mutations in the RNA splicing factors SRSF2, SF3B1, and U2AF1 are the most frequent class of mutations in myelodysplastic syndromes and are also common in clonal hematopoiesis, acute myeloid leukemia, chronic lymphocytic leukemia, and a variety of solid tumors. They cause genome-wide splicing alterations that affect important regulators of hematopoiesis. Several mRNA isoforms promoted by the various splicing factor mutants comprise a premature termination codon (PTC) and are therefore potential targets of nonsense-mediated mRNA decay (NMD). In light of the mechanistic relationship between splicing and NMD, we sought evidence for a specific role of mutant SRSF2 in NMD. We show that SRSF2 Pro95 hot spot mutations elicit enhanced mRNA decay, which is dependent on sequence-specific RNA binding and splicing. SRSF2 mutants enhance the deposition of exon junction complexes (EJCs) downstream from the PTC through RNA-mediated molecular interactions. This architecture then favors the association of key NMD factors to elicit mRNA decay. Gene-specific blocking of EJC deposition by antisense oligonucleotides circumvents aberrant NMD promoted by mutant SRSF2, restoring the expression of PTC-containing transcript. Our study uncovered critical effects of SRSF2 mutants in hematologic malignancies, reflecting the regulation at multiple levels of RNA metabolism, from splicing to decay.
ISSN:0890-9369
1549-5477
DOI:10.1101/gad.332270.119