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: L T Timchenko, J W Miller, N A Timchenko, D R DeVore, K V Datar, L Lin, R Roberts, C T Caskey, M S Swanson
• Journal: Nucleic acids research (Nucleic Acids Res) Vol. 24 Issue 22 Pg. 4407-14 (Nov 15 1996) ISSN: 0305-1048 [Print] England
• PMID: 8948631 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• CELF1 Protein
• CELF1 protein, human
• Heterogeneous-Nuclear Ribonucleoproteins
• Neoplasm Proteins
• RNA Precursors
• RNA-Binding Proteins
• Ribonucleoproteins

Topics

• Amino Acid Sequence
• CELF1 Protein
• HeLa Cells
• Heterogeneous-Nuclear Ribonucleoproteins
• Humans
• Molecular Sequence Data
• Myotonic Dystrophy (genetics)
• Neoplasm Proteins (metabolism)
• RNA Precursors (chemistry, isolation & purification, metabolism)
• RNA-Binding Proteins (chemistry, genetics)
• Ribonucleoproteins (chemistry, genetics, metabolism)
• Trinucleotide Repeats