Structural and functional basis of mammalian microRNA biogenesis by Dicer

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Authors

ZAPLETAL David TABORSKA Eliska PASULKA Josef MALIK Radek KUBÍČEK Karel ZÁNOVÁ Martina MUCH Christian ŠEBESTA Marek BUCCHERI Valeria HORVAT Filip JENICKOVA Irena PROCHAZKOVA Michaela PROCHAZKA Jan PINKAS Matyáš NOVÁČEK Jiří JOSEPH Diego F SEDLACEK Radislav BERNECKY Carrie CARROLL Donal ŠTEFL Richard SVOBODA Petr

Year of publication 2022
Type Article in Periodical
Magazine / Source Molecular Cell
MU Faculty or unit

Central European Institute of Technology

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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