Structural and functional basis of mammalian microRNA biogenesis by Dicer

0567393 - ÚMG 2023 RIV US eng J - Journal Article
Zapletal, D. - Táborská, Eliška - Pasulka, Josef - Malík, Radek - Kubíček, Karel - Zanova, M. - Much, C. - Šebesta, M. - Buccheri, Valeria - Horvat, Filip - Jeníčková, Irena - Procházková, Michaela - Procházka, Jan - Pinkas, M. - Nováček, J. - Florian Joseph, Diego André - Sedláček, Radislav - Bernecky, C. - O'Carroll, D. - Štefl, R. - Svoboda, Petr
Structural and functional basis of mammalian microRNA biogenesis by Dicer.
Molecular Cell. Roč. 82, č. 21 (2022), s. 4064-4079e.13. ISSN 1097-2765. E-ISSN 1097-4164
R&D Projects: GA MŠMT(CZ) LM2018126; GA MŠMT(CZ) LM2018131; GA ČR GX20-03950X; GA MŠMT EF18_046/0015861
EU Projects: European Commission(XE) 647403 - D-FENS
Research Infrastructure: e-INFRA CZ - 90140; CIISB II - 90127
Institutional support: RVO:68378050
Keywords : cryo-em structure * guide strand selection * rna-binding * structure validation * expression * molprobity * trbp complex * mouse * specifity
OECD category: Biochemistry and molecular biology
Impact factor: 16, year: 2022
Method of publishing: Open access
https://doi.org/10.1016/j.molcel.2022.10.010

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.
Permanent Link: https://hdl.handle.net/11104/0338651