Published online before print July 9, 2009

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(American Journal of Pathology. 2009;175:748-762.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.090047

Expression of RNA CCUG Repeats Dysregulates Translation and Degradation of Proteins in Myotonic Dystrophy 2 Patients

Elizabeth Salisbury^*, Benedikt Schoser, Christiane Schneider-Gold, Guo-Li Wang^*, Claudia Huichalaf, Bingwen Jin, Mario Sirito^¶, Partha Sarkar^||, Ralf Krahe^¶, Nikolai A. Timchenko^* and Lubov T. Timchenko

From the Departments of Pathology,^* and Molecular Physiology and Biophysics, Huffington Center on Aging, Baylor College of Medicine, Houston, Texas; the Department of Neurology, Ludwig-Maximilians-University, Munich, Germany; the Department of Neurology, St. Josef Hospital of the Ruhr- University of Bochum, Bochum, Germany; the Department of Genetics,^¶ University of Texas M.D. Anderson Cancer Center, Houston, Texas; and the Department of Neurology,|| University of Texas Medical Branch, Galveston, Texas

Myotonic dystrophy 2 (DM2) is a multisystem skeletal muscle disease caused by an expansion of tetranucleotide CCTG repeats, the transcription of which results in the accumulation of untranslated CCUG RNA. In this study, we report that CCUG repeats both bind to and misregulate the biological functions of cytoplasmic multiprotein complexes. Two CCUG-interacting complexes were subsequently purified and analyzed. A major component of one of the complexes was found to be the 20S catalytic core complex of the proteasome. The second complex was found to contain CUG triplet repeat RNA-binding protein 1 (CUGBP1) and the translation initiation factor eIF2. Consistent with the biological functions of the 20S proteasome and the CUGBP1-eIF2 complexes, the stability of short-lived proteins and the levels of the translational targets of CUGBP1 were shown to be elevated in DM2 myoblasts. We found that the overexpression of CCUG repeats in human myoblasts from unaffected patients, in C2C12 myoblasts, and in a DM2 mouse model alters protein translation and degradation, similar to the alterations observed in DM2 patients. Taken together, these findings show that RNA CCUG repeats misregulate protein turnover on both the levels of translation and proteasome-mediated protein degradation.