Molecular basis of indispensable accuracy of mammalian miRNA biogenesis

Zapletal, D.; Svobodova, E.; Pasulka, J.; Malik, R.; Kubicek, K.; Zanova, M.; Much, C.; Sebesta, M.; Buccheri, V.; Horvat, F.; Jenickova, I.; Prochazkova, M.; Prochazka, J.; Pinkas, M.; Novacek, J.; Joseph, D. F.; Sedlacek, R.; O'Carroll, D.; Stefl, R.; Svoboda, P.

doi:10.1101/2022.04.13.488181

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bioRxiv · 10.1101/2022.04.13.488181

Molecular basis of indispensable accuracy of mammalian miRNA biogenesis

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Abstract

Mammalian Dicer is the gatekeeper into the essential gene-regulating miRNA pathway. What is committing mammalian Dicer to the miRNA pathway remains unknown. We report that Dicers highly conserved DExD/H helicase domain is the key structural element supporting accurate miRNA biogenesis. While ATPase activity of the domain is non-essential, its loss is lethal in mice. It is required during canonical miRNA biogenesis for efficient recognition, high-fidelity cleavage, and strand selection. Structure of Dicer-miRNA precursor complexes showed that the DExD/H domain acquired helicase-unrelated function defining Dicer conformations, which affect substrate loading and facilitate pre-selection of miRNA precursors. Dicer lacking the DExD/H domain favors conformations enabling reduced substrate selectivity and supporting RNA interference, a different small RNA pathway. Therefore, Dicers DExD/H domain ensures indispensable high-fidelity precursor processing of mammalian miRNAs, which constitutes a structural "mold" for adaptive miRNA evolution.

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Zapletal, D., Svobodova, E., Pasulka, J., Malik, R., Kubicek, K., Zanova, M., Much, C., Sebesta, M., Buccheri, V., Horvat, F., Jenickova, I., Prochazkova, M., Prochazka, J., Pinkas, M., Novacek, J., Joseph, D. F., Sedlacek, R., O'Carroll, D., Stefl, R., Svoboda, P.. 2022-04-13. Molecular basis of indispensable accuracy of mammalian miRNA biogenesis. https://doi.org/10.1101/2022.04.13.488181

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