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Alternative Splicing of hnRNPA2/B1 by SRSF2 and Its Effects on Stress Granule Formation in Myelodysplasia
Author(s) -
Ardasheva Anastasia,
Vasic Radovan,
Halene Stephanie
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.598.2
Subject(s) - stress granule , rna splicing , gene isoform , alternative splicing , sr protein , exon , rna binding protein , microbiology and biotechnology , biology , genetics , gene , rna , messenger rna , translation (biology)
Myelodysplastic syndrome (MDS) is a type of hematopoietic malignancy commonly diagnosed in patients >65 years old. Although the exact cause for MDS is not known, mutations in the cell splicing machinery are a common feature among patients diagnosed with this disease. One of the most common mutations occurs in the serine/arginine‐rich splicing factor 2 (SRSF2), converting Proline 95 to Histidine. We previously identified recurrent mis‐splicing of the heterogeneous ribonuclear protein A2/B1 (hnRNPA2/B1) in patients bearing the SRSF2 P95H mutation. In the actively translating cell, hnRNPA2/B1 is capable of forming non‐membrane droplets called stress granules that preserve stalled translational complexes under conditions stress. The four isoforms of hnRNPA2B1 are characterized by the presence or absence of exons 2 & 9. Studies on neuronal cells have shown that these isoforms localize differently within the cell under homeostatic conditions. We therefore hypothesized that the alternative splicing of hnRNPA2/B1 in patients bearing the SRSF2 mutation results in the expression of isoforms with altered ability to participate in stress granule formation, resulting in consequent defects in RNA metabolism. To assess the ability of the four isoforms to participate in stress granules, we transfected 293FT mammalian cells with each isoform and assessed cellular localization following induction of stress granule formation with sodium arsenite treatment. These experiments may allow for a greater understanding of the mechanisms that contribute to cellular dysfunction in MDS.