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The helicase domain of Dicer ensures strict processing of evolutionarily optimized microRNAs

ABSTRACT: Ribonuclease Dicer generates small RNAs for RNA interference (RNAi) and microRNA (miRNA) pathways. Mammalian Dicer produces miRNAs but its tripartite N-terminal helicase domain inhibits processing of double-stranded RNA for RNAi. Mouse oocytes express Dicer, which enhances RNAi because it lacks the helicase’s proximal subdomain HEL1. Here we show that genetic removal of HEL1 in mice causes 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. Essential is the HEL1 structure, not its helicase activity, because mutations of critical aminoacids do not affect viability or fertility and have minimal impact on miRNA biogenesis. Altogether, HEL1 is a critical structural component of Dicer in its role of a highly conserved structural “mold” that ensures high-fidelity processing and adaptive evolution of mammalian miRNA precursors.

ORGANISM(S): Mus musculus

PROVIDER: GSE243016 | GEO | 2024/04/10

REPOSITORIES: GEO

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

Project description: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.

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A retrotransposon-driven Dicer variant enhances endogenous RNAi in mouse oocytes

Project description:Mammals have one Dicer gene required for biogenesis of small RNAs in microRNA (miRNA) and RNA interference (RNAi) pathways. Yet, endogenous RNAi is highly active in oocytes but not in somatic cells. Here, we provide a mechanistical explanation for high RNAi activity in mouse oocytes. The main Dicer isoform in oocytes is transcribed from an intronic MT-C retrotransposon, which functions as a promoter of an oocyte-specific Dicer isoform (denoted DicerO). DicerO lacks an N-terminal helicase domain and has a higher cleavage activity than the full-length Dicer from somatic cells. DicerO can rescue the miRNA pathway and, in addition, it efficiently produces small RNAs from long dsRNA substrates. Thus, control of endogenous RNAi activity in mice occurs via alternative Dicer isoform and the phylogenetic origin of DicerO demonstrates evolutionary plasticity of RNA silencing pathways.

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DICER-interacting partners in juvenile mouse testes

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