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Tytuł pozycji:

Titration of SF3B1 Activity Reveals Distinct Effects on the Transcriptome and Cell Physiology.

Tytuł:
Titration of SF3B1 Activity Reveals Distinct Effects on the Transcriptome and Cell Physiology.
Autorzy:
Kim Guisbert KS; Department of Biomedical and Chemical Engineering and Sciences, Florida Institute of Technology, Melbourne, FL 32937, USA.
Mossiah I; Department of Biomedical and Chemical Engineering and Sciences, Florida Institute of Technology, Melbourne, FL 32937, USA.
Guisbert E; Department of Biomedical and Chemical Engineering and Sciences, Florida Institute of Technology, Melbourne, FL 32937, USA.
Źródło:
International journal of molecular sciences [Int J Mol Sci] 2020 Dec 17; Vol. 21 (24). Date of Electronic Publication: 2020 Dec 17.
Typ publikacji:
Journal Article
Język:
English
Imprint Name(s):
Original Publication: Basel, Switzerland : MDPI, [2000-
MeSH Terms:
Alternative Splicing*
Cell Physiological Phenomena*
Gene Expression Regulation/*drug effects
Phosphoproteins/*metabolism
RNA Splicing Factors/*metabolism
RNA, Messenger/*metabolism
Sequence Analysis, RNA/*methods
Transcriptome/*drug effects
Epoxy Compounds/pharmacology ; HEK293 Cells ; Humans ; Macrolides/pharmacology ; Nonsense Mediated mRNA Decay ; Phosphoproteins/genetics ; RNA Splicing Factors/genetics ; RNA, Messenger/genetics
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Grant Information:
R15 CA227573 United States CA NCI NIH HHS; Finken Endowment Fund Community Foundation for Brevard
Contributed Indexing:
Keywords: HSR; NMD; SF3B1; alternative splicing; early transcription termination; heat shock response; nonsense-mediated decay; pladienolide B; proteostasis
Substance Nomenclature:
0 (Epoxy Compounds)
0 (Macrolides)
0 (Phosphoproteins)
0 (RNA Splicing Factors)
0 (RNA, Messenger)
0 (SF3B1 protein, human)
0 (pladienolide B)
Entry Date(s):
Date Created: 20201222 Date Completed: 20210318 Latest Revision: 20210318
Update Code:
20240105
PubMed Central ID:
PMC7766730
DOI:
10.3390/ijms21249641
PMID:
33348896
Czasopismo naukowe
SF3B1 is a core component of the U2 spliceosome that is frequently mutated in cancer. We have previously shown that titrating the activity of SF3B1, using the inhibitor pladienolide B (PB), affects distinct steps of the heat shock response (HSR). Here, we identify other genes that are sensitive to different levels of SF3B1 (5 vs. 100 nM PB) using RNA sequencing. Significant changes to mRNA splicing were identified at both low PB and high PB concentrations. Changes in expression were also identified in the absence of alternative splicing, suggesting that SF3B1 influences other gene expression pathways. Surprisingly, gene expression changes identified in low PB are not predictive of changes in high PB. Specific pathways were identified with differential sensitivity to PB concentration, including nonsense-mediated decay and protein-folding homeostasis, both of which were validated using independent reporter constructs. Strikingly, cells exposed to low PB displayed enhanced protein-folding capacity relative to untreated cells. These data reveal that the transcriptome is exquisitely sensitive to SF3B1 and suggests that the activity of SF3B1 is finely regulated to coordinate mRNA splicing, gene expression and cellular physiology.
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