Non-canonical miRNA biogenesis mechanisms in Drosophila and mammals

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PROJECT ABSTRACT microRNAs (miRNAs) are an abundant class of small regulatory RNAs that typically derive from stepwise cleavages of hairpin transcripts by the Drosha and Dicer RNase III enzymes. The resulting mature miRNAs mediate extensive networks of post- transcriptional regulation, and are implicated in a variety of diseases including cancer. This proposal extends our long-standing commitment to understanding atypical strategies for microRNA biogenesis, and their implications during normal and dysfunctional settings. For example, our past efforts uncovered diverse non-canonical substrates that bypass Drosha and/or Dicer to yield active microRNAs. In current efforts, we report unexpected insights into selective processing by Drosha and Dicer. First, we gain insights from a non-canonical miRNA to propose a new general model for nuclear microRNA biogenesis by Drosha and its cofactor DGCR8 at operons, which involves novel cofactors. Second, we build on the observation that catalytic inactivation of Dicer is selected in cancer to uncover selective biogenesis effects and unexpected molecular and phenotypic consequences. We will dissect the models of underlying biogenesis mechanisms, and evaluate the broader impacts of these regulatory strategies using genomic strategies. Overall, by better understanding how microRNAs are generated, we will improve our capacity to harness them experimentally, as well as help interpret recurrent diseases linked to mutation of core microRNA biogenesis factors.