myotonic dystrophy - IDMC.org

Abstract No : 28
ORAL PRESENTATIONS
THE ROLE OF PROTEIN-PROTEIN COMPLEXES IN MYOTONIC
DYSTROPHIES 1 AND 2
Salisbury E., Schoser B.G.H., Nguyen H., Sakai K., Agulion C., Schneider-Gold C.,
Timchenko N.A. and Timchenko L.T.
Baylor College of Medicine, Dep. of Medicine, Rm 536D, One Baylor Plaza, Houston, TX , USA, 77030
DM1 and DM2 are caused by an expansion of polymorphic CTG (DM1) and CCTG (DM2)
repeats. We have found that, similar to CUG repeats in DM1, the expanded RNA CCUG
repeats are expressed in nuclei and in cytoplasm of DM2 cells. RNA CUG and CCUG triplet
repeats cause pathogenesis of DM1 and DM2 through disruption of biological functions
of RNA-binding proteins. We have observed that protein levels of CUG triplet repeat
binding protein, CUGBP1, are increased in DM1 and DM2 patients. Investigations of
CUGBP1 transgenic mice showed that the elevation of CUGBP1 is involved in a delay of
muscle development and differentiation and in muscular dystrophy. These symptoms are
associated with CUGBP1-dependent increase of translation of MEF2A, C/EBP beta and
p21. CUGBP1 regulates translation of these proteins through a formation of a high MW
CUGBP1-eIF2 complex which consists of CUGBP1, eIF2 alpha, eIF2 beta, eIF2 gamma,
CRT, eR60, grp78 and eR90. The CUGBP1-eIF2 complex specifically interacts with the 5’
regions of C/EBP beta and p21 mRNAs and increases translation of these proteins. Our
data suggest that, in DM2 cells, CCUG expansion affects biological functions of cytoplasmic
CUGBP1-eIF2 complex as well as biological functions of high MW complexes in
nuclei. These data are consistent with the hypothesis that expanded RNA CUG and CCUG
repeats might destroy biological processes in DM1 and DM2 patients by disruption of
multimeric protein-protein complexes.
QUEBEC 2005 49