Honors Theses (Chemistry)

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Myotonic Dystrophy: The Structure of CUG Repeats in Solution
(2007-03) Truong, Brian
Myotonic dystrophy (DM), a genetic and neuromuscular disorder, is the most common form of adult-onset muscular dystrophy resulting in symptoms such as proximal muscle weakness, myotonia, iridescent cataracts and cardiac arrhythmia. Myotonic dystrophy type 1 (DM1), the most prevalent type of DM, is caused by a (CTG)n expansion in the 3â untranslated region of the dystrophin myotonin protein kinase gene. At the RNA level, the CUG repeats form a stem-loop that is thought to be the pathogenic element. Previous work in the Berglund Lab determined the crystal structure of CUG repeats and found these repeats form a structure similar to standard double-stranded A-form nucleic acid. However, since crystal structures may be misleading, we verify A-form conformation using a solution-based assay. A-form double-stranded RNA (dsRNA) is known to be cleaved into small RNA molecules in cells; therefore, the cellular machinery that recognizes and cleaves these dsRNA should degrade expanded CUG repeats. To test this hypothesis, we use an enzyme called Dicer that recognizes and cleaves A-form dsRNA. The cleavage of r(CUG)54 by Dicer confirms CUG repeats adopt a conformation similar to A-form in solution. The structure of CUG repeats may therefore lead to the design of potential drugs for DM.