Dataset Information

Ubiquitous expression of CUG or CAG trinucleotide repeat RNA causes common morphological defects in a Drosophila model of RNA-mediated pathology.

ABSTRACT: Expanded DNA repeat sequences are known to cause over 20 diseases, including Huntington's disease, several types of spinocerebellar ataxia and myotonic dystrophy type 1 and 2. A shared genetic basis, and overlapping clinical features for some of these diseases, indicate that common pathways may contribute to pathology. Multiple mechanisms, mediated by both expanded homopolymeric proteins and expanded repeat RNA, have been identified by the use of model systems, that may account for shared pathology. The use of such animal models enables identification of distinct pathways and their 'molecular hallmarks' that can be used to determine the contribution of each pathway in human pathology. Here we characterise a tergite disruption phenotype in adult flies, caused by ubiquitous expression of either untranslated CUG or CAG expanded repeat RNA. Using the tergite phenotype as a quantitative trait we define a new genetic system in which to examine 'hairpin' repeat RNA-mediated cellular perturbation. Further experiments use this system to examine whether pathways involving Muscleblind sequestration or Dicer processing, which have been shown to mediate repeat RNA-mediated pathology in other model systems, contribute to cellular perturbation in this model.

SUBMITTER: Lawlor KT

PROVIDER: S-EPMC3371033 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Ubiquitous expression of CUG or CAG trinucleotide repeat RNA causes common morphological defects in a Drosophila model of RNA-mediated pathology.

Lawlor Kynan T KT O'Keefe Louise V LV Samaraweera Saumya E SE van Eyk Clare L CL Richards Robert I RI

PloS one 20120608 6

Expanded DNA repeat sequences are known to cause over 20 diseases, including Huntington's disease, several types of spinocerebellar ataxia and myotonic dystrophy type 1 and 2. A shared genetic basis, and overlapping clinical features for some of these diseases, indicate that common pathways may contribute to pathology. Multiple mechanisms, mediated by both expanded homopolymeric proteins and expanded repeat RNA, have been identified by the use of model systems, that may account for shared pathol ...[more]

PMID: 22715390

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Project description:Expansions of RNA AUUCU, CCUG, CAG, and CUG repeats cause spinocerebellar ataxia type 10, myotonic dystrophy type 2, Huntington's disease, and myotonic dystrophy type 1, respectively. By performing extensive molecular dynamic simulations, we investigated the bending propensities and conformational landscapes adopted by 3×3, 2×2, and 1×1 internal loops observed in RNA AUUCU, CCUG, CAG, and CUG repeat expansions using model systems having biologically relevant repeat sizes. We show that the conformational variability experienced by these loops is more complex than previous reports where a variety of unconventional hydrogen bonds are formed. At the global scale, strong bending propensity was observed in r(AUUCU)10, r(CCUG)15, r(CAG)20, and r(CUG)20, and, to a lesser extent, in r(AUUCU)4, r(CCUG)10, r(CAG)10, and r(CUG)10. Furthermore, RNA CAG repeats exhibit a tendency toward bent states with more than 50% of observed conformations having bending angles greater than 50°, while RNA CUG repeats display relatively linear-like conformations with extremely bent conformations accounting for less than 25% of the observed structures. Conformations experienced by RNA AUUCU repeats are a combination of strongly bent and kinked structures. The bent states in RNA CCUG repeats mostly fall into the moderately bent category with a marginal ensemble experiencing extreme bending. The general pattern observed in all the bent structures indicates the collapse of the major groove width as the mechanical trigger for bending, which is caused by alteration of base pair step parameters at multiple locations along the RNA due to local distortions at the loop sites. Overextension is also observed in all the RNA repeats that is attributed to widening of the major groove width as well as undertwisting phenomenon. This information and the rich structural repository could be applied for structure based small molecule design targeting disease-causing RNAs. The bending propensities of these constructs, at the global level, could also have implications on how expanded RNA repeats interact with proteins.

Dataset Information

Ubiquitous expression of CUG or CAG trinucleotide repeat RNA causes common morphological defects in a Drosophila model of RNA-mediated pathology.

Publications

Ubiquitous expression of CUG or CAG trinucleotide repeat RNA causes common morphological defects in a Drosophila model of RNA-mediated pathology.

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