The abnormal expression of microRNAs (miRNAs), small non-coding RNAs responsible for regulating gene expression, has been implicated in the development and progression of various diseases including cancer. Our understanding of miRNA expression and processing relies on RNA recognition and cleavage by dedicated enzymes to produce the mature miRNA that goes on to target complementary mRNAs. One critical step in miRNA maturation involves Dicer-mediated cleavage of the precursor miRNA (pre-miRNA) by recognition of specific features in the stem-loop structure of the RNA. However, several recent reports have shown that a subset of pre-miRNAs can form an alternative G-quadruplex (G4) structure, creating an equilibrium between the canonical and noncanonical structures, thereby inhibiting Dicer-mediated recognition and cleavage. This may present a new avenue for regulation of miRNA maturation and expression. To investigate the biological role of these G4s in pre-miRNA processing, we used a small molecule microarray screen to identify molecules that bind specifically to either the G4 or stem-loop structure in target pre-miRNAs of interest. These compounds were analyzed for their ability to bind to the G4 or stem-loop and to modify the structural equilibrium in the pre-miRNA. We are further examining how small molecule induced changes in pre-miRNA structure can alter miRNA maturation by examining Dicer-mediated cleavage of the RNA. These RNA-binding probes will be useful tools in exploring this structure-based mechanism for pre-miRNA regulation, particularly in disease states where these miRNAs exhibit aberrant expression.

Development of chemical tools to investigate alternative structures in disease relevant precursor microRNAs

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