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김은희

Kim, Eunhee
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SRSF2 Mutations Contribute to Myelodysplasia by Mutant-Specific Effects on Exon Recognition

Author(s)
Kim, EunheeIlagan, Janine O.Liang, YangDaubner, Gerrit M.Lee, Stanley C. -W.Ramakrishnan, AravindLi, YueChung, Young RockMicol, Jean-BaptisteMurphy, Michele E.Cho, HanaKim, Min-KyungZebari, Ahmad S.Aumann, ShlomzionPark, Christopher Y.Buonamici, SilviaSmith, Peter G.Deeg, H. JoachimLobry, CamilleAifantis, IannisModis, YorgoAllain, Frederic H. -T.Halene, StephanieBradley, Robert K.Abdel-Wahab, Omar
Issued Date
2015-05
DOI
10.1016/j.ccell.2015.04.006
URI
https://scholarworks.unist.ac.kr/handle/201301/20163
Citation
CANCER CELL, v.27, no.5, pp.617 - 630
Abstract
Mutations 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 missplicing 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
Publisher
CELL PRESS
ISSN
1535-6108
Keyword
METHYLTRANSFERASE GENE EZH2PRE-MESSENGER-RNAU2AF1 MUTATIONSELEMENTSSC35TRANSFORMATIONDISORDERSNEOPLASMSPROTEINSSF3B1

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