title: SR proteins are NXF1 adaptors that link alternative RNA processing to mRNA export.
abstract: Nuclear export factor 1 (NXF1) exports mRNA to the cytoplasm after recruitment to mRNA by specific adaptor proteins. How and why cells use numerous different export adaptors is poorly understood. Here we critically evaluate members of the SR protein family (SRSF1-7) for their potential to act as NXF1 adaptors that couple pre-mRNA processing to mRNA export. Consistent with this proposal, >1000 endogenous mRNAs required individual SR proteins for nuclear export in vivo. To address the mechanism, transcriptome-wide RNA-binding profiles of NXF1 and SRSF1-7 were determined in parallel by individual-nucleotide-resolution UV cross-linking and immunoprecipitation (iCLIP). Quantitative comparisons of RNA-binding sites showed that NXF1 and SR proteins bind mRNA targets at adjacent sites, indicative of cobinding. SRSF3 emerged as the most potent NXF1 adaptor, conferring sequence specificity to RNA binding by NXF1 in last exons. Interestingly, SRSF3 and SRSF7 were shown to bind different sites in last exons and regulate 3' untranslated region length in an opposing manner. Both SRSF3 and SRSF7 promoted NXF1 recruitment to mRNA. Thus, SRSF3 and SRSF7 couple alternative splicing and polyadenylation to NXF1-mediated mRNA export, thereby controlling the cytoplasmic abundance of transcripts with alternative 3' ends.
authors.affiliation: RNA Regulation Group, Institute of Cell Biology and Neuroscience, Goethe-University Frankfurt, 60438 Frankfurt/Main, Germany;
authors.forename: Michaela
authors.initials: M
authors.lastname: Müller-McNicoll
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut 06520, USA;
authors.forename: Valentina
authors.initials: V
authors.lastname: Botti
authors.affiliation: Institute of Molecular Biology (IMB), 55128 Mainz, Germany;
authors.forename: Antonio M
authors.initials: AM
authors.lastname: de Jesus Domingues
authors.affiliation: Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany;
authors.forename: Holger
authors.initials: H
authors.lastname: Brandl
authors.affiliation: RNA Regulation Group, Institute of Cell Biology and Neuroscience, Goethe-University Frankfurt, 60438 Frankfurt/Main, Germany; Buchmann Institute for Life Sciences (BMLS), 60438 Frankfurt/Main, Germany;
authors.forename: Oliver D
authors.initials: OD
authors.lastname: Schwich
authors.affiliation: Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany;
authors.forename: Michaela C
authors.initials: MC
authors.lastname: Steiner
authors.affiliation: Faculty of Computer and Information Science, University of Ljubljana, Ljubljana 1000, Slovenia.
authors.forename: Tomaz
authors.initials: T
authors.lastname: Curk
authors.affiliation: Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany;
authors.forename: Ina
authors.initials: I
authors.lastname: Poser
authors.affiliation: Buchmann Institute for Life Sciences (BMLS), 60438 Frankfurt/Main, Germany;
authors.forename: Kathi
authors.initials: K
authors.lastname: Zarnack
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut 06520, USA;
authors.forename: Karla M
authors.initials: KM
authors.lastname: Neugebauer
mesh_terms: D020413:3' Untranslated Regions; D021581:Active Transport, Cell Nucleus / Q000235:genetics; D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D002460:Cell Line; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism; D029543:Nucleocytoplasmic Transport Proteins / Q000378:metabolism*; D011485:Protein Binding; D012333:RNA, Messenger / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000378:metabolism*; D015203:Reproducibility of Results; D012261:Ribonucleoproteins / Q000378:metabolism; D000068103:Serine-Arginine Splicing Factors
chemical_list: D020413:3' Untranslated Regions; C569386:NXF1 protein, mouse; D009687:Nuclear Proteins; D029543:Nucleocytoplasmic Transport Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D012261:Ribonucleoproteins; C499372:SRSF2 protein, mouse; D000068103:Serine-Arginine Splicing Factors
keywords: NXF1; SR protein; SRSF3; SRSF7; alternative 3′ end processing; iCLIP; mRNA export