Human Dicer1 hotspot mutation induces both loss and gain of miRNA function.

ABSTRACT: The core miRNA biogenesis enzyme Dicer1 sustains recurrent mutations in cancer that compromise its RNase IIIb domain, which cleaves 5p arms of pre-miRNA hairpins. However, the lack of knockin models has limited fuller understanding. Here, we generated Dicer1-KO and Dicer1-S1344L (homozygous and hemizygous) human ESCs; the latter is a non-catalytic mutation in RNase IIIa that impairs RNase IIIb activity. Dicer1 knockouts lack canonical miRNAs, while S1344L induces two trends: ablation of miRNA-5p strands, and selective changes in miRNA-3p strands. Curiously, we recognized directional upregulation of miRNA-3p passenger strands, indicating a broad strand switch. We used multiple in vitro assays to show 3p arm-nicked pre-miRNAs preferentially load miRNA-3p species i

SUBMITTER: Jee D 

PROVIDER: S-EPMC12632780 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature