Cardiac elav-type RNA-binding protein (ETR-3) binds to RNA CUG repeats expanded in myotonic dystrophy.
Myotonic dystrophy (DM) is a neuromuscular disorder associated with CTG triplet repeat expansion in the myotonin protein kinase gene ( DMPK ). We previously proposed a hypothesis suggesting that the expanded CUG repeats sequester specific RNA-binding proteins and that such a sequestration results in abnormal RNA processing of several RNAs containing CUG repeats in multiple tissues affected in patients with DM. One of the members of the CUG-binding proteins, CUG-BP, has been identified previously. Here we describe the second member of this family, elav -type ribonucleoprotein (ETR-3), which is highly expressed in heart and is able to interact with CUG repeats. Screening of a mouse liver cDNA library with a CUG-BP probe identified two mETR-3 cDNAs. Two additional cDNAs from mouse heart were amplified by RT-PCR. These cDNAs differ by several insertions/deletions and might be generated via alternative splicing. Mouse ETR-3 has a mol. wt of 50 kDa and displays a high level of homology to CUG-BP protein. The organization of the RNA-binding domains (RBDs) within the ETR-3 molecule is similar to one within CUG-BP. A study of mETR-3 RNA-binding activity showed that the mETR-3 binds to (CUG)8repeats. Sequence analysis of mETR-3 indicates the presence of several CUG repeats within the mETR-3 mRNA. Both CUG-BP and mETR-3 bind to mETR-3 mRNA via CUG repeats, suggesting the possible involvement of CUG-BP-like proteins in the regulation of mETR-3 processing. Analysis of the tissue distribution of ETR-3 showed that in human cells, ETR-3 mRNA is highly expressed in heart, but is undetectable in other tissues examined. Our results suggest the existence of a family of proteins that bind to CUG repeats and might be affected in DM by expansion of CUG repeats.
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Departments of Medicine, Section of Cardiology and Pathology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Timchenko
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Timchenko
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D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D000067878:CELF Proteins; D017931:DNA Primers / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008969:Molecular Sequence Data; D009206:Myocardium / Q000378:metabolism; D009223:Myotonic Dystrophy / Q000235:genetics* / Q000378:metabolism*; D009419:Nerve Tissue Proteins; D012313:RNA / Q000235:genetics* / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D019680:Trinucleotide Repeat Expansion
D000067878:CELF Proteins; C117363:CELF2 protein, human; D017931:DNA Primers; D018076:DNA, Complementary; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D012313:RNA