Expansion of CUG RNA repeats causes stress and inhibition of translation in myotonic dystrophy 1 (DM1) cells
ABSTRACT The purpose of this study was to investigate the role of the mutant CUGn RNA in the induction of stress in type 1 myotonic dystrophy (DM1) cells and in the stress-mediated inhibition of protein translation in DM1. To achieve our goals, we performed HPLC-based purification of stress granules (SGs), immunoanalysis of SGs with stress markers TIA-1, CUGBP1, and ph-eIF2, site-specific mutagenesis, and examinations of RNA-protein and protein-protein interactions in myoblasts from control and DM1 patients. The cause-and-effect relationships were addressed in stable cells expressing mutant CUG repeats. We found that the mutant CUGn RNA induces formation of SGs through the increase of the double-stranded RNA-dependent protein kinase (PKR) and following inactivation of eIF2α, one of the substrates of PKR. We show that SGs trap mRNA coding for the DNA repair and remodeling factor MRG15 (MORF4L1), translation of which is regulated by CUGBP1. As the result of the trapping, the levels of MRG15 are reduced in DM1 cells and in CUG-expressing cells. These data show that CUG repeats cause stress in DM1 through the PKR-ph-eIF2α pathway inhibiting translation of certain mRNAs, such as MRG15 mRNA. The repression of protein translation by stress might contribute to the progressive muscle loss in DM1.
- SourceAvailable from: Rosanna CardaniFrontiers in Aging Neuroscience 07/2014; 6:196. DOI:10.3389/fnagi.2014.00196 · 2.84 Impact Factor
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ABSTRACT: RNA-binding proteins CUG-binding protein 1 (CUGBP1) and HuR are highly expressed in epithelial tissues and modulate the stability and translation of target mRNAs. Here, we present evidence that CUGBP1 and HuR jointly regulate the translation of occludin and play a crucial role in the maintenance of tight junction (TJ) integrity in the intestinal epithelial cell monolayer. CUGBP1 and HuR competed for association with the same occludin 3'-untranslated region element and regulated occludin translation competitively and in opposite directions. CUGBP1 overexpression decreased HuR binding to occludin mRNA, repressed occludin translation, and compromised the TJ barrier function, whereas HuR overexpression inhibited CUGBP1 association with occludin mRNA and promoted occludin translation, thereby enhancing the barrier integrity. Repression of occludin translation by CUGBP1 was due to the colocalization of CUGBP1 and tagged occludin RNA in processing bodies (P-bodies), and this colocalization was prevented by HuR overexpression. These findings indicate that CUGBP1 represses occludin translation by increasing occludin mRNA recruitment to P-bodies, whereas HuR promotes occludin translation by blocking occludin mRNA translocation to P-bodies via the displacement of CUGBP1.Molecular biology of the cell 11/2012; 24(2). DOI:10.1091/mbc.E12-07-0531 · 5.98 Impact Factor
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ABSTRACT: This review is intended to increase awareness of the value of parasitological studies of the Atlantic cod, which has an exceptionally rich and varied parasite fauna compared with most other species of marine fish. We list 107 named species of protozoan and metazoan parasites recorded from cod, plus many that have been identified to generic or higher taxonomic levels only. This diversity is apparently linked to the omnivorous diet of cod, its occurrence at low salinities where it is exposed to infection by euryhaline parasites that most marine fish do not encounter, and its status as one of the most abundant and widespread piscivorous species in the North Atlantic. Parasitological studies of cod have been undertaken mainly in response to concerns about public health and spoilage effects of the more common and obvious parasites. We also review more academic aspects such as the host range and specificity of cod parasites, their life cycles, zoogeography, population dynamics and host sexual differences to parasitic infection. We also deal in depth with applied aspects such as the role of parasites as pathogens and their use as biological tags in population studies of cod and as indicators of marine pollution. We suggest areas in which further study is most urgently required and try to anticipate which parasites are likely to become important pathogens in the developing mariculture of cod.Advances in Marine Biology 01/2001; DOI:10.1016/S0065-2881(01)40002-2 · 5.00 Impact Factor
Claudia H. Huichalaf