TY - JOUR
T1 - Expression of RNA CCUG repeats dysregulates translation and degradation of proteins in myotonic dystrophy 2 patients
AU - Salisbury, Elizabeth
AU - Schoser, Benedikt
AU - Schneider-Gold, Christiane
AU - Wang, Guo Li
AU - Huichalaf, Claudia
AU - Jin, Bingwen
AU - Sirito, Mario
AU - Sarkar, Partha
AU - Krahe, Ralf
AU - Timchenko, Nikolai A.
AU - Timchenko, Lubov T.
N1 - Funding Information:
Supported by National Institutes of Health grants AR052791, NS063298 (to L.T.T.), GM55188, CA100070, and AG025477 (to N.A.T.); grants from the Deutsche Gesellschaft fur Muskelkranke (to B.S.); the Muscular Dystrophy Association (to R.K.); and the Kleberg Foundation (to R.K.). B.S. is member of the German network on muscular dystrophies (MD-NET, 01GM0601).
PY - 2009/8
Y1 - 2009/8
N2 - 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.
AB - 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.
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U2 - 10.2353/ajpath.2009.090047
DO - 10.2353/ajpath.2009.090047
M3 - Article
C2 - 19590039
AN - SCOPUS:67650751240
SN - 0002-9440
VL - 175
SP - 748
EP - 762
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 2
ER -