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Reversal of RNA dominance by displacement of protein sequestered on triplet repeat RNA.

ABSTRACT: Genomic expansions of simple tandem repeats can give rise to toxic RNAs that contain expanded repeats. In myotonic dystrophy, the expression of expanded CUG repeats (CUGexp) causes abnormal regulation of alternative splicing and neuromuscular dysfunction. We used a transgenic mouse model to show that derangements of myotonic dystrophy are reversed by a morpholino antisense oligonucleotide, CAG25, that binds to CUGexp RNA and blocks its interaction with muscleblind-like 1 (MBNL1), a CUGexp-binding protein. CAG25 disperses nuclear foci of CUGexp RNA and reduces the overall burden of this toxic RNA. As MBNL1 is released from sequestration, the defect of alternative splicing regulation is corrected, thereby restoring ion channel function. These findings suggest an alternative use of antisense methods, to inhibit deleterious interactions of proteins with pathogenic RNAs.

SUBMITTER: Wheeler TM

PROVIDER: S-EPMC4109973 | biostudies-literature | 2009 Jul

REPOSITORIES: biostudies-literature

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Reversal of RNA dominance by displacement of protein sequestered on triplet repeat RNA.

Wheeler Thurman M TM Sobczak Krzysztof K Lueck John D JD Osborne Robert J RJ Lin Xiaoyan X Dirksen Robert T RT Thornton Charles A CA

Science (New York, N.Y.) 20090701 5938

Genomic expansions of simple tandem repeats can give rise to toxic RNAs that contain expanded repeats. In myotonic dystrophy, the expression of expanded CUG repeats (CUGexp) causes abnormal regulation of alternative splicing and neuromuscular dysfunction. We used a transgenic mouse model to show that derangements of myotonic dystrophy are reversed by a morpholino antisense oligonucleotide, CAG25, that binds to CUGexp RNA and blocks its interaction with muscleblind-like 1 (MBNL1), a CUGexp-bindin ...[more]

PMID: 19608921

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