Smaug/SAMD4A restores translational activity of CUGBP1 and suppresses CUG-induced myopathy.

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 us...

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Autores principales:	Maria de Haro, Ismael Al-Ramahi, Karlie R Jones, Jerrah K Holth, Lubov T Timchenko, Juan Botas
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Genetics QH426-470
Acceso en línea:	https://doaj.org/article/81c1a1b7cb6448209d9e1e44202c3f53
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spelling	oai:doaj.org-article:81c1a1b7cb6448209d9e1e44202c3f532021-11-18T06:19:44ZSmaug/SAMD4A restores translational activity of CUGBP1 and suppresses CUG-induced myopathy.1553-73901553-740410.1371/journal.pgen.1003445https://doaj.org/article/81c1a1b7cb6448209d9e1e44202c3f532013-04-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23637619/?tool=EBIhttps://doaj.org/toc/1553-7390https://doaj.org/toc/1553-7404We 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.Maria de HaroIsmael Al-RamahiKarlie R JonesJerrah K HolthLubov T TimchenkoJuan BotasPublic Library of Science (PLoS)articleGeneticsQH426-470ENPLoS Genetics, Vol 9, Iss 4, p e1003445 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Genetics QH426-470
spellingShingle	Genetics QH426-470 Maria de Haro Ismael Al-Ramahi Karlie R Jones Jerrah K Holth Lubov T Timchenko Juan Botas Smaug/SAMD4A restores translational activity of CUGBP1 and suppresses CUG-induced myopathy.
description	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.
format	article
author	Maria de Haro Ismael Al-Ramahi Karlie R Jones Jerrah K Holth Lubov T Timchenko Juan Botas
author_facet	Maria de Haro Ismael Al-Ramahi Karlie R Jones Jerrah K Holth Lubov T Timchenko Juan Botas
author_sort	Maria de Haro
title	Smaug/SAMD4A restores translational activity of CUGBP1 and suppresses CUG-induced myopathy.
title_short	Smaug/SAMD4A restores translational activity of CUGBP1 and suppresses CUG-induced myopathy.
title_full	Smaug/SAMD4A restores translational activity of CUGBP1 and suppresses CUG-induced myopathy.
title_fullStr	Smaug/SAMD4A restores translational activity of CUGBP1 and suppresses CUG-induced myopathy.
title_full_unstemmed	Smaug/SAMD4A restores translational activity of CUGBP1 and suppresses CUG-induced myopathy.
title_sort	smaug/samd4a restores translational activity of cugbp1 and suppresses cug-induced myopathy.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/81c1a1b7cb6448209d9e1e44202c3f53
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Smaug/SAMD4A restores translational activity of CUGBP1 and suppresses CUG-induced myopathy.

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