title: Identification of a (CUG)n triplet repeat RNA-binding protein and its expression in myotonic dystrophy.
abstract: Myotonic dystrophy (DM) is an autosomal dominant neuromuscular disease that is associated with a (CTG)n repeat expansion in the 3'-untranslated region of the myotonin protein kinase (Mt-PK) gene. This study reports the isolation and characterization of a (CUG)n triplet repeat pre-mRNA/mRNA binding protein that may play an important role in DM pathogenesis. Two HeLa cell proteins, CUG-BP1 and CUG-BP2, have been purified based upon their ability to bind specifically to (CUG)8 oligonucleotides in vitro. While CUG-BP1 is the major (CUG)8-binding activity in normal cells, nuclear CUG-BP2 binding activity increases in DM cells. Both CUG-BP1 and CUG-BP2 have been identified as isoforms of a novel heterogeneous nuclear ribonucleoprotein (hnRNP), hNab50. The CUG-BP/hNab50 protein is localized predominantly in the nucleus and is associated with polyadenylated RNAs in vivo. In vitro RNA-binding/photocrosslinking studies demonstrate that CUG-BP/hNab50 binds to RNAs containing the Mt-PK 3'-UTR. We propose that the (CUG)n repeat region in Mt-PK mRNA is a binding site for CUG-BP/hNab50 in vivo, and triplet repeat expansion leads to sequestration of this hnRNP on mutant Mt-PK transcripts.
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: L T
authors.initials: LT
authors.lastname: Timchenko
authors.forename: J W
authors.initials: JW
authors.lastname: Miller
authors.forename: N A
authors.initials: NA
authors.lastname: Timchenko
authors.forename: D R
authors.initials: DR
authors.lastname: DeVore
authors.forename: K V
authors.initials: KV
authors.lastname: Datar
authors.forename: L
authors.initials: L
authors.lastname: Lin
authors.forename: R
authors.initials: R
authors.lastname: Roberts
authors.forename: C T
authors.initials: CT
authors.lastname: Caskey
authors.forename: M S
authors.initials: MS
authors.lastname: Swanson
mesh_terms: D000595:Amino Acid Sequence; D000067879:CELF1 Protein; D006367:HeLa Cells; D034441:Heterogeneous-Nuclear Ribonucleoproteins; D006801:Humans; D008969:Molecular Sequence Data; D009223:Myotonic Dystrophy / Q000235:genetics*; D009363:Neoplasm Proteins / Q000378:metabolism; D012322:RNA Precursors / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000737:chemistry* / Q000235:genetics; D012261:Ribonucleoproteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D018911:Trinucleotide Repeats
chemical_list: D000067879:CELF1 Protein; C102843:CELF1 protein, human; D034441:Heterogeneous-Nuclear Ribonucleoproteins; D009363:Neoplasm Proteins; D012322:RNA Precursors; D016601:RNA-Binding Proteins; D012261:Ribonucleoproteins