title: Defining early steps in mRNA transport: mutant mRNA in myotonic dystrophy type I is blocked at entry into SC-35 domains.
abstract: In myotonic dystrophy type 1 (DM1), triplet repeat expansion in the 3' untranslated region of dystrophia myotonica protein kinase (DMPK) causes the nuclear retention of mutant messenger RNA (mRNA). Although the DMPK gene locus positions precisely at the outer edge of a factor-rich SC-35 domain, the normal mRNA consistently accumulates within the domain, and this RNA is depleted upon transcriptional inhibition. In DM1, mutant transcripts detach from the gene but accumulate in granules that abut but do not enter SC-35 domains, suggesting that RNA entry into the domain is blocked. Despite their exclusion from these compartments, mutant transcripts are spliced. MBNL1 (muscleblind-like protein 1) is an alternative splicing factor that becomes highly concentrated with mutant RNA foci. Small interfering RNA-mediated knockdown of MBNL1 promotes the accumulation or entry of newly synthesized mutant transcripts in the SC-35 domain. Collectively, these data suggest that an initial step in the intranuclear path of some mRNAs is passage from the gene into an SC-35 domain and implicate these structures in postsplicing steps before export.
authors.affiliation: Department of Cell Biology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Kelly P
authors.initials: KP
authors.lastname: Smith
authors.forename: Meg
authors.initials: M
authors.lastname: Byron
authors.forename: Carol
authors.initials: C
authors.lastname: Johnson
authors.forename: Yigong
authors.initials: Y
authors.lastname: Xing
authors.forename: Jeanne B
authors.initials: JB
authors.lastname: Lawrence
mesh_terms: D002478:Cells, Cultured; D002648:Child; D006801:Humans; D008297:Male; D008958:Models, Molecular; D009154:Mutation; D032448:Myoblasts, Skeletal / Q000378:metabolism; D009223:Myotonic Dystrophy / Q000235:genetics / Q000378:metabolism*; D065636:Myotonin-Protein Kinase; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D012326:RNA Splicing; D034443:RNA Transport; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D019680:Trinucleotide Repeat Expansion
chemical_list: C585517:DMPK protein, human; C493663:MBNL1 protein, human; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D065636:Myotonin-Protein Kinase; D017346:Protein Serine-Threonine Kinases