Structural and functional basis of mammalian microRNA biogenesis by Dicer
| Authors | |
|---|---|
| Year of publication | 2022 |
| Type | Article in Periodical |
| Magazine / Source | Molecular Cell |
| MU Faculty or unit | |
| Citation | |
| web | https://www.sciencedirect.com/science/article/pii/S1097276522009674?via%3Dihub |
| Doi | http://dx.doi.org/10.1016/j.molcel.2022.10.010 |
| Keywords | CRYO-EM STRUCTUREGUIDE STRAND SELECTIONRNA-BINDINGSTRUCTURE VALIDATIONTRBP COMPLEXMOUSEEXPRESSIONMOLPROBITYSPECIFICITYRECOGNITION |
| Description | MicroRNA (miRNA) and RNA interference (RNAi) pathways rely on small RNAs produced by Dicer endonucle-ases. Mammalian Dicer primarily supports the essential gene-regulating miRNA pathway, but how it is spe-cifically adapted to miRNA biogenesis is unknown. We show that the adaptation entails a unique structural role of Dicer???s DExD/H helicase domain. Although mice tolerate loss of its putative ATPase function, the com-plete absence of the domain is lethal because it assures high-fidelity miRNA biogenesis. Structures of murine Dicerd???miRNA precursor complexes revealed that the DExD/H domain has a helicase-unrelated structural function. It locks Dicer in a closed state, which facilitates miRNA precursor selection. Transition to a cleav-age-competent open state is stimulated by Dicer-binding protein TARBP2. Absence of the DExD/H domain or its mutations unlocks the closed state, reduces substrate selectivity, and activates RNAi. Thus, the DExD/H domain structurally contributes to mammalian miRNA biogenesis and underlies mechanistical partitioning of miRNA and RNAi pathways. |
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