title: Smaug/SAMD4A restores translational activity of CUGBP1 and suppresses CUG-induced myopathy.
abstract: We report the identification and characterization of a previously unknown suppressor of myopathy caused by expansion of CUG repeats, the mutation that triggers Myotonic Dystrophy Type 1 (DM1). We screened a collection of genes encoding RNA-binding proteins as candidates to modify DM1 pathogenesis using a well established Drosophila model of the disease. The screen revealed smaug as a powerful modulator of CUG-induced toxicity. Increasing smaug levels prevents muscle wasting and restores muscle function, while reducing its function exacerbates CUG-induced phenotypes. Using human myoblasts, we show physical interactions between human Smaug (SMAUG1/SMAD4A) and CUGBP1. Increased levels of SMAUG1 correct the abnormally high nuclear accumulation of CUGBP1 in myoblasts from DM1 patients. In addition, augmenting SMAUG1 levels leads to a reduction of inactive CUGBP1-eIF2α translational complexes and to a correction of translation of MRG15, a downstream target of CUGBP1. Therefore, Smaug suppresses CUG-mediated muscle wasting at least in part via restoration of translational activity of CUGBP1.
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.
authors: Maria
authors: M
authors: de Haro
authors: Ismael
authors: I
authors: Al-Ramahi
authors: Karlie R
authors: KR
authors: Jones
authors: Jerrah K
authors: JK
authors: Holth
authors: Lubov T
authors: LT
authors: Timchenko
authors: Juan
authors: J
authors: Botas
mesh_terms: D005786:Gene Expression Regulation; D006801:Humans; D032446:Myoblasts / Q000378:metabolism; D009223:Myotonic Dystrophy / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics
chemical_list: D016601:RNA-Binding Proteins
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