Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 102, Issue 46, Pages 16626-16631Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0505873102
Keywords
toxic RNA; U-U mismatches; x-ray crystallography
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Funding
- NIAMS NIH HHS [R01 AR053903] Funding Source: Medline
- NIGMS NIH HHS [R01 GM021967, R01 GM020066, GM21967] Funding Source: Medline
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Myotonic dystrophy (DIM) type 1 is associated with an expansion of (> 50) CTG repeats within the 3' untranslated region (UTR) of the dstrophin myotonin protein kinase gene (dmpk). In the corresponding mRNA transcript, the CUG repeats form an extended stem-loop structure. The double-stranded RNA of the stem sequesters RNA binding proteins away from their normal cellular targets resulting in aberrant transcription, alternative splicing patterns, or both, thereby leading to DM. To better understand the structural basis of DM type 1, we determined to 1.58-angstrom resolution the x-ray crystal structure of an 18-bp RNA containing six CUG repeats. The CUG repeats form antiparallel double-stranded helices that stack end-on-end in the crystal to form infinite, pseudocontinuous helices similar to the long CUG stem loops formed by the expanded CUG repeats in DM type 1. The CUG helix is very similar in structure to A-form RNA with the exception of the unique U-U mismatches. This structure provides a high-resolution view of a toxic, trinucleotide repeat RNA.
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