The helicase domain of Dicer ensures essential accuracy of miRNA biogenesis in mice

Dicer ribonucleases, which generate small RNAs for the RNA interference (RNAi) and microRNA (miRNA) pathways, often have an N-terminal DExD helicase subdomain (also called HEL1). In the mammalian Dicer, HEL1 inhibits RNAi while it appears unnecessary for miRNA biogenesis. To determine its functional significance, we genetically eliminated HEL1 from Dicer in mice. We observed embryonic growth retardation, defects in the cardiopulmonary system, and perinatal lethality. HEL1 suppresses biogenesis of mirtrons, a non-canonical low-abundant class of miRNAs, and is required for high-fidelity cleavage and strand selection during biogenesis of canonical miRNAs. The HEL1 domain itself is essential rather than its helicase activity, because mutations of critical catalytic amino acids do not affect mouse viability or fertility and have minimal impact on miRNA biogenesis. Therefore, HEL1 is a critical structural component of the mammalian Dicer, supporting its role of a conserved structural “mold” that ensures high-fidelity processing and adaptive evolution of mammalian miRNA precursors. Refer to individual Series