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      Protein 4.1R Exon 16 3′ Splice Site Activation Requires Coordination among TIA1, Pcbp1, and RBM39 during Terminal Erythropoiesis

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          ABSTRACT

          Exon 16 of protein 4.1R encodes a spectrin/actin-binding peptide critical for erythrocyte membrane stability. Its expression during erythroid differentiation is regulated by alternative pre-mRNA splicing. A UUUUCCCCCC motif situated between the branch point and the 3′ splice site is crucial for inclusion. We show that the UUUU region and the last three C residues in this motif are necessary for the binding of splicing factors TIA1 and Pcbp1 and that these proteins appear to act in a collaborative manner to enhance exon 16 inclusion. This element also activates an internal exon when placed in a corresponding intronic position in a heterologous reporter. The impact of these two factors is further enhanced by high levels of RBM39, whose expression rises during erythroid differentiation as exon 16 inclusion increases. TIA1 and Pcbp1 associate in a complex containing RBM39, which interacts with U2AF65 and SF3b155 and promotes U2 snRNP recruitment to the branch point. Our results provide a mechanism for exon 16 3′ splice site activation in which a coordinated effort among TIA1, Pcbp1, and RBM39 stabilizes or increases U2 snRNP recruitment, enhances spliceosome A complex formation, and facilitates exon definition through RBM39-mediated splicing regulation.

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          Author and article information

          Journal
          Mol Cell Biol
          Mol. Cell. Biol
          mcb
          mcb
          MCB
          Molecular and Cellular Biology
          American Society for Microbiology (1752 N St., N.W., Washington, DC )
          0270-7306
          1098-5549
          13 February 2017
          14 April 2017
          1 May 2017
          : 37
          : 9
          : e00446-16
          Affiliations
          [a ]Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
          [b ]Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA
          [c ]Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
          [d ]Dana-Farber/Harvard Cancer Center, Boston, Massachusetts, USA
          Author notes
          Address correspondence to Shu-Ching Huang, shu-ching_huang@ 123456dfci.harvard.edu .
          [*]

          Present address: Henry S. Zhang, University of South Carolina School of Medicine, Columbia, South Carolina, USA; Ellen McMahon, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA; Jennie Park Ou, Stony Brook University Hospital, Stony Brook, New York, USA.

          H.S.Z., B.Y., and E.M. contributed equally to this article.

          Citation Huang S-C, Zhang HS, Yu B, McMahon E, Nguyen DT, Yu FH, Ou AC, Ou JP, Benz EJ, Jr. 2017. Protein 4.1R exon 16 3′ splice site activation requires coordination among TIA1, Pcbp1, and RBM39 during terminal erythropoiesis. Mol Cell Biol 37:e00446-16. https://doi.org/10.1128/MCB.00446-16.

          Article
          PMC5394280 PMC5394280 5394280 00446-16
          10.1128/MCB.00446-16
          5394280
          28193846
          96a28bfb-0e49-4704-a3df-26a8ccf26613
          Copyright © 2017 American Society for Microbiology.

          All Rights Reserved.

          History
          : 4 August 2016
          : 29 August 2016
          : 3 February 2017
          Page count
          Figures: 12, Tables: 1, Equations: 0, References: 63, Pages: 21, Words: 11799
          Funding
          Funded by: HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI) https://doi.org/10.13039/100000050
          Award ID: HL24385
          Award Recipient : Edward J. Benz
          Funded by: Dana-Farber Cancer Institute (DFCI) https://doi.org/10.13039/100007886
          Award ID: Claudia Adams Barr Award
          Award Recipient : Shu-Ching Huang
          Categories
          Research Article
          Custom metadata
          May 2017

          RBM39,alternative splicing,erythropoiesis,Pcbp1,protein 4.1R,TIA1

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