title: Regulation of mRNA Levels by Decay-Promoting Introns that Recruit the Exosome Specificity Factor Mmi1.
abstract: In eukaryotic cells, inefficient splicing is surprisingly common and leads to the degradation of transcripts with retained introns. How pre-mRNAs are committed to nuclear decay is unknown. Here, we uncover a mechanism by which specific intron-containing transcripts are targeted for nuclear degradation in fission yeast. Sequence elements within these "decay-promoting" introns co-transcriptionally recruit the exosome specificity factor Mmi1, which induces degradation of the unspliced precursor and leads to a reduction in the levels of the spliced mRNA. This mechanism negatively regulates levels of the RNA helicase DDX5/Dbp2 to promote cell survival in response to stress. In contrast, fast removal of decay-promoting introns by co-transcriptional splicing precludes Mmi1 recruitment and relieves negative expression regulation. We propose that decay-promoting introns facilitate the regulation of gene expression. Based on the identification of multiple additional Mmi1 targets, including mRNAs, long non-coding RNAs, and sn/snoRNAs, we suggest a general role in RNA regulation for Mmi1 through transcript degradation.
authors.affiliation: Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Kilchert
authors.affiliation: Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.
authors.forename: Sina
authors.initials: S
authors.lastname: Wittmann
authors.affiliation: Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.
authors.forename: Monica
authors.initials: M
authors.lastname: Passoni
authors.affiliation: Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.
authors.forename: Sneha
authors.initials: S
authors.lastname: Shah
authors.affiliation: Institute for Structural and Molecular Biology, Centre for Synthetic and Systems Biology (SynthSys), C.H. Waddington Building, the King's Buildings, Mayfield Road, Edinburgh EH9 3BF, UK. Electronic address: sgrannem@staffmail.ed.ac.uk.
authors.forename: Sander
authors.initials: S
authors.lastname: Granneman
authors.affiliation: Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK. Electronic address: lidia.vasilieva@bioch.ox.ac.uk.
authors.forename: Lidia
authors.initials: L
authors.lastname: Vasiljeva
mesh_terms: D001483:Base Sequence; D047369:Chromatin Immunoprecipitation; D053487:DEAD-box RNA Helicases / Q000378:metabolism; D055354:Exosomes / Q000378:metabolism*; D015966:Gene Expression Regulation, Fungal; D007438:Introns; D011485:Protein Binding; D012322:RNA Precursors / Q000378:metabolism; D012326:RNA Splicing; D020871:RNA Stability; D012333:RNA, Messenger / Q000378:metabolism*; D022661:RNA, Untranslated / Q000378:metabolism; D012568:Schizosaccharomyces / Q000235:genetics / Q000378:metabolism*; D029702:Schizosaccharomyces pombe Proteins / Q000235:genetics / Q000378:metabolism*; D017423:Sequence Analysis, RNA; D059467:Transcriptome; D039221:mRNA Cleavage and Polyadenylation Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: C512176:Mmi1 protein, S pombe; D012322:RNA Precursors; D012333:RNA, Messenger; D022661:RNA, Untranslated; D029702:Schizosaccharomyces pombe Proteins; D039221:mRNA Cleavage and Polyadenylation Factors; D053487:DEAD-box RNA Helicases
keywords: Mmi1; RNA decay; RNA exosome; intron retention; mRNA; splicing