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Regulation of microRNA biogenesis and its crosstalk with other cellular pathways

Abstract

MicroRNAs (miRNAs) are short non-coding RNAs that inhibit the expression of target genes by directly binding to their mRNAs. miRNAs are transcribed as precursor molecules, which are subsequently cleaved by the endoribonucleases Drosha and Dicer. Mature miRNAs are bound by a member of the Argonaute (AGO) protein family to form the RNA-induced silencing complex (RISC) in a process termed RISC loading. Advances in structural analyses of Drosha and Dicer complexes enabled elucidation of the mechanisms that drive these molecular machines. Transcription of miRNAs, their processing by Drosha and Dicer and RISC loading are key steps in miRNA biogenesis, and various additional factors facilitate, support or inhibit these processes. Recent work has revealed that regulatory factors not only coordinate individual miRNA processing steps but also connect miRNA biogenesis with other cellular processes. Protein phosphorylation, for example, links miRNA biogenesis to various signalling pathways, and such modifications are often associated with disease. Furthermore, not all miRNAs follow canonical processing routes, and many non-canonical miRNA biogenesis pathways have recently been characterized.

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Acknowledgements

The authors apologize to those whose work was not included or cited owing to space constraints. The authors’ research is supported by grants from the European Research Council (ERC) (‘moreRNA’ 930806), the Deutsche Forschungsgemeinschaft (DFG) (FOR2127, SFB960 and SPP1935) and the Bavarian Research Network for Molecular Biosystems (BioSysNet).

Reviewer information

Nature Reviews Molecular Cell Biology thanks W. Filipowicz, G. Michlewski and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Author information

G.M., N.T. and T.T. researched data for the article; G.M., N.T. and T.T. made substantial contributions to the discussion of content; G.M. and T.T. wrote the manuscript; and G.M., N.T. and T.T. reviewed and edited the manuscript before submission.

Competing interests

The authors declare no competing interests.

Correspondence to Gunter Meister.

Glossary

Argonaute

(AGO). A large family of proteins involved in small-RNA-guided gene silencing. Argonaute proteins are highly conserved and found in Eukarya, Archaea and Bacteria.

PIWI–Argonaute–Zwille

(PAZ). A domain named after the PIWI, Argonaute and Zwille proteins that is characteristic of Argonaute proteins and also found in some Dicer enzymes. The domain anchors the 3ʹend of the bound small RNA.

P element-induced wimpy testes

(PIWI). A domain characteristic of Argonaute proteins. PIWI domains are structurally similar to RNase H, and some possess catalytic activity.

Electron microscopy density maps

In electron microscopy, higher electron density leads to stronger absorption and scattering by interaction of the beam with electrons of the sample. Electron density maps are a 3D reconstruction of the signal, which is the basis for structure model building.

RNA exosome

An abundant 3ʹ– 5ʹ exoribonuclease complex that is found in all Eukarya as well as in some Archaea.

Crosslinking and immunoprecipitation

A method used to identify RNA sites that are bound by proteins.

Import receptor

A protein that transports another protein or RNA molecule (cargo) from the cytoplasm into the nucleus.

Debranching

The release of the 2ʹ−5ʹ phosphodiester linkage of the intron lariat during pre-mRNA splicing.

Intron lariat

A lariat structure that is formed in the intron during splicing by covalent linkage of the 5ʹ end of the intron and a 2ʹ hydroxyl group of an intronic internal adenosine.

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Further reading

Fig. 1: Canonical microRNA biogenesis.
Fig. 2: Molecular machines of microRNA processing.
Fig. 3: Post-translational modification of canonical microRNA processing factors.
Fig. 4: RNA-binding proteins that regulate microRNA biogenesis.
Fig. 5: Non-canonical microRNA biogenesis.