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bioRxiv · 10.1101/2021.08.30.458106

Flanking sequences regulate the toxicity, non-ATG translation, and aggregation of RNA with tandem CAG Repeats

Das, M. R.·Chang, Y.·Saunders, R.·Zhang, N.·Tomberlin, C.·Vale, R. D.·Jain, A.
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Abstract

Nucleotide repeat-expansions cause several neurodegenerative disorders, including Huntingtons disease and spinocerebellar ataxia. The expanded repeat-containing RNA transcribed from the affected loci agglomerate in the nucleus as pathogenic foci. Here we demonstrate that depending on their surrounding sequence context, RNAs with expanded CAG repeats can also undergo nuclear export and aggregate in the cytoplasm. Cytoplasmic aggregation of repeat-containing RNA coincides with several disease hallmarks, including repeat-associated non-AUG (RAN) translation, mislocalization of RNA binding proteins, and cell toxicity. Interestingly, the repeat-containing RNA co-aggregate with RAN translation products. Inhibition of RAN translation prevents cytoplasmic RNA aggregation and also alleviates cell toxicity. Our findings provide a cogent explanation for aberrant cytoplasmic localization of RNA binding proteins and implicate cis-acting flanking sequences in mediating RAN translation and disease.

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Das, M. R., Chang, Y., Saunders, R., Zhang, N., Tomberlin, C., Vale, R. D., Jain, A.. 2021-08-31. Flanking sequences regulate the toxicity, non-ATG translation, and aggregation of RNA with tandem CAG Repeats. https://doi.org/10.1101/2021.08.30.458106

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