DICER's dual-pocket mechanism refines microRNA cleavage fidelity
Nature reports that human DICER uses two distinct 5′-end binding pockets (a G-favoured pocket promoting DC21 and a U-favoured pocket promoting DC22), and that RNA motifs like mWCU and YCR, along with coordinated dsRBD/PAZ domain motions, influence cleavage site selection. Massively parallel dicing assays and cryo-EM reveal how the 5′-nt identity can override or be overridden by motifs, driving precise but flexible processing of substrates and offering insights for shRNA design across species.