title: RNA steady-state defects in myotonic dystrophy are linked to nuclear exclusion of SHARP.
abstract: We describe a new mechanism by which CTG tract expansion affects myotonic dystrophy (DM1). Changes to the levels of a panel of RNAs involved in muscle development and function that are downregulated in DM1 are due to aberrant localization of the transcription factor SHARP (SMART/HDAC1-associated repressor protein). Mislocalization of SHARP in DM1 is consistent with increased CRM1-mediated export of SHARP to the cytoplasm. A direct link between CTG repeat expression and SHARP mislocalization is demonstrated as expression of expanded CTG repeats in normal cells recapitulates cytoplasmic SHARP localization. These results demonstrate a role for the inactivation of SHARP transcription in DM1 biology.
authors.affiliation: Department of Biochemistry and Molecular Biology, Institute for Genetic Medicine, 2250 Alcazar Street, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA.
authors.forename: Warunee
authors.initials: W
authors.lastname: Dansithong
authors.forename: Sonali P
authors.initials: SP
authors.lastname: Jog
authors.forename: Sharan
authors.initials: S
authors.lastname: Paul
authors.forename: Robabeh
authors.initials: R
authors.lastname: Mohammadzadeh
authors.forename: Stephanie
authors.initials: S
authors.lastname: Tring
authors.forename: Yukwah
authors.initials: Y
authors.lastname: Kwok
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Fry
authors.forename: Paul
authors.initials: P
authors.lastname: Marjoram
authors.forename: Lucio
authors.initials: L
authors.lastname: Comai
authors.forename: Sita
authors.initials: S
authors.lastname: Reddy
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D002467:Cell Nucleus / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D032446:Myoblasts / Q000378:metabolism; D009223:Myotonic Dystrophy / Q000235:genetics / Q000503:physiopathology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects; D012313:RNA / Q000378:metabolism*; D012326:RNA Splicing / Q000235:genetics; D016601:RNA-Binding Proteins / Q000378:metabolism; D019680:Trinucleotide Repeat Expansion / Q000235:genetics
chemical_list: D000903:Antibiotics, Antineoplastic; D004268:DNA-Binding Proteins; D005231:Fatty Acids, Unsaturated; D018398:Homeodomain Proteins; C467324:MBNL3 protein, human; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; C106687:SIX5 protein, human; C476510:SPEN protein, human; D012313:RNA; C038753:leptomycin B