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Originally published In Press as doi:10.1074/jbc.M005960200 on December 21, 2000

J. Biol. Chem., Vol. 276, Issue 11, 7820-7826, March 16, 2001
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RNA CUG Repeats Sequester CUGBP1 and Alter Protein Levels and Activity of CUGBP1*

Nikolai A. TimchenkoDagger , Zong-Jin Cai§, Alana L. WelmDagger , Sita Reddy, Tetsuo Ashizawa||, and Lubov T. Timchenko§**

From the Departments of Dagger  Pathology and Huffington Center on Aging, § Medicine, Section of Cardiovascular Sciences, and || Neurology, Baylor College of Medicine, Houston, Texas 77030 and the  Department of Biochemistry and Molecular Biology, University of Southern California, School of Medicine, Los Angeles, California 90033

An RNA CUG triplet repeat binding protein, CUGBP1, regulates splicing and translation of various RNAs. Expansion of RNA CUG repeats in the 3'-untranslated repeat of the mutant myotonin protein kinase (DMPK) mRNA in myotonic dystrophy (DM) is associated with alterations in binding activity of CUGBP1. To investigate whether CUGBP1 is directly affected by expansion of CUG repeats in DM tissues, we examined the intracellular status of CUGBP1 in DM patients as well as in cultured cells over expressing RNA CUG repeats. The analysis of RNA·protein complexes showed that, in control tissues, the majority of CUGBP1 is free of RNA, whereas in DM patients the majority of CUGBP1 is associated with RNA containing CUG repeats. Similarly to DM patients, overexpression of RNA CUG repeats in cultured cells results in the re-allocation of CUGBP1 from a free state to the RNA·protein complexes containing CUG repeats. CUG repeat-dependent translocation of CUGBP1 into RNA·protein complexes is associated with increased levels of CUGBP1 protein and its binding activity. Experiments with cyclohexamide-dependent block of protein synthesis showed that the half-life of CUGBP1 is increased in cells expressing CUG repeats. Alteration of CUGBP1 in DM is accompanied by alteration in translation of a transcription factor CCAAT/enhancer-binding protein beta  (C/EBPbeta ), which has been previously described to be a target of CUGBP1. Analysis of C/EBPbeta isoforms in DM patients with altered levels of CUGBP1 showed that translation of a dominant negative isoform, LIP, is induced by CUGBP1. Results of this paper demonstrate that the expansion of CUG repeats in DM affects RNA-binding proteins and leads to alteration in RNA processing.

* This work was supported by National Institute of Health Grants AR10D44387 (to L. T. T.), AG16392 (to L. T. T.), AG00756-01 (to N. A. T.), and GM55188-01 (to N. A. T.) and by grants from the Muscular Dystrophy Association (to L. T. T.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

** To whom correspondence should be addressed: Section of Cardiovascular Sciences, Dept. of Medicine, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. Tel.: 713-798-6911; Fax: 713-798-3142; E-mail: lubovt@bcm.tmc.edu.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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