Recurrent SRSF2 mutations in MDS affect both splicing and NMD Journal Article
| Authors: | Rahman, M. A.; Lin, K. T.; Bradley, R. K.; Abdel-Wahab, O.; Krainer, A. R. |
| Article Title: | Recurrent SRSF2 mutations in MDS affect both splicing and NMD |
| Abstract: | 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. © 2020 Rahman et al. |
| Keywords: | controlled study; leukemia; unclassified drug; gene mutation; human cell; exon; mutation; core protein; binding affinity; complex formation; protein protein interaction; rna interference; myelodysplastic syndrome; regulatory mechanism; messenger rna; alternative rna splicing; binding site; molecular interaction; nonsense mutation; rna metabolism; genomic dna; rna binding; myelodysplastic syndromes; complementary dna; proline; messenger rna precursor; splicing; fusion protein; transcription factor ezh2; antisense oligonucleotide; nonsense mediated mrna decay; serine arginine rich protein; coat protein; splicing factor; human; female; priority journal; article; rna sequencing; hela cell line; rna splicing factor; srsf2; intron retention; maltose binding protein; molm-13 cell line; rna isoform; k-562 cell line; nonsense-mediatedmrnadecay; ms2 protein; rna splicing factor srsf2 |
| Journal Title: | Genes and Development |
| Volume: | 34 |
| Issue: | 5 |
| ISSN: | 0890-9369 |
| Publisher: | Cold Spring Harbor Laboratory Press |
| Date Published: | 2020-03-01 |
| Start Page: | 413 |
| End Page: | 427 |
| Language: | English |
| DOI: | 10.1101/gad.332270.119 |
| PUBMED: | 32001512 |
| PROVIDER: | scopus |
| PMCID: | PMC7050488 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 April 2020 -- Source: Scopus |
