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Global Promotion of Alternative Internal Exon Usage by mRNA 3' End Formation Factors
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UMass Chan Affiliations
Department of Molecular, Cell and Cancer BiologyDocument Type
Journal ArticlePublication Date
2015-06-04Keywords
*Alternative SplicingBase Sequence
Cleavage And Polyadenylation Specificity Factor
Exons
Genes, Reporter
Green Fluorescent Proteins
HEK293 Cells
Humans
Nuclear Proteins
Protein Binding
RNA Splice Sites
RNA, Messenger
RNA-Binding Proteins
Repressor Proteins
Ribonucleoprotein, U1 Small Nuclear
Ribonucleoproteins
Sequence Analysis, RNA
Cell Biology
Cellular and Molecular Physiology
Computational Biology
Genomics
Molecular Biology
Molecular Genetics
Metadata
Show full item recordAbstract
The mechanisms that regulate alternative precursor mRNA (pre-mRNA) splicing are largely unknown. Here, we perform an RNAi screen to identify factors required for alternative splicing regulation by RBFOX2, an RNA-binding protein that promotes either exon inclusion or exclusion. Unexpectedly, we find that two mRNA 3' end formation factors, cleavage and polyadenylation specificity factor (CPSF) and SYMPK, are RBFOX2 cofactors for both inclusion and exclusion of internal exons. RBFOX2 interacts with CPSF/SYMPK and recruits it to the pre-mRNA. RBFOX2 and CPSF/SYMPK then function together to regulate binding of the early intron recognition factors U2AF and U1 small nuclear ribonucleoprotein particle (snRNP). Genome-wide analysis reveals that CPSF also mediates alternative splicing of many internal exons in the absence of RBFOX2. Accordingly, we show that CPSF/SYMPK is also a cofactor of NOVA2 and heterologous nuclear ribonucleoprotein A1 (HNRNPA1), RNA-binding proteins that also regulate alternative splicing. Collectively, our results reveal an unanticipated role for mRNA 3' end formation factors in global promotion of alternative splicing.Source
Mol Cell. 2015 Jun 4;58(5):819-31. doi: 10.1016/j.molcel.2015.03.016. Epub 2015 Apr 23. Link to article on publisher's siteDOI
10.1016/j.molcel.2015.03.016Permanent Link to this Item
http://hdl.handle.net/20.500.14038/36542PubMed ID
25921069Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1016/j.molcel.2015.03.016
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