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Modulation of microRNA processing and expression through RNA editing by ADAR deaminases

Nature Structural & Molecular Biology volume 13, pages 13–21 (2006)Cite this article

Abstract

Adenosine deaminases acting on RNA (ADARs) are involved in editing of adenosine residues to inosine in double-stranded RNA (dsRNA). Although this editing recodes and alters functions of several mammalian genes, its most common targets are noncoding repeat sequences, indicating the involvement of this editing system in currently unknown functions other than recoding of protein sequences. Here we show that specific adenosine residues of certain microRNA (miRNA) precursors are edited by ADAR1 and ADAR2. Editing of pri–miR-142, the precursor of miRNA-142, expressed in hematopoietic tissues, resulted in suppression of its processing by Drosha. The edited pri–miR-142 was degraded by Tudor-SN, a component of RISC and also a ribonuclease specific to inosine-containing dsRNAs. Consequently, mature miRNA-142 expression levels increased substantially in ADAR1 null or ADAR2 null mice. Our results demonstrate a new function of RNA editing in the control of miRNA biogenesis.

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Figure 1: A → I RNA editing of pri-miR RNAs by ADAR.
Figure 2: Analysis of pri–miR-142 processing in HEK293 cells.
Figure 3: In vitro processing of pri–miR-142 RNAs by miRNA processor complexes.
Figure 4: Suppression of pri–miR-142 processing in HEK293 cells transfected with ADAR expression plasmids.
Figure 5: Degradation of highly edited pri–miR-142 RNAs by TSN.
Figure 6: Increased expression levels of miR-142 RNAs in spleen and thymus of ADAR null mice.

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Acknowledgements

We thank J.M. Murray for critical reading of the manuscript and J.T. Lee for excellent technical assistance. This work was supported in part by grants from the US National Institutes of Health, the March of Dimes and the Commonwealth Universal Research Enhancement Program of the Pennsylvania Department of Health.

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Authors and Affiliations

  1. The Wistar Institute, 3601 Spruce Street, Philadelphia, 19104, Pennsylvania, USA

    Weidong Yang, Thimmaiah P Chendrimada, Qingde Wang, Ramin Shiekhattar & Kazuko Nishikura

  2. Department of Molecular Neurobiology, Max Planck Institute for Medical Research, Jahnstrasse 29, Heidelberg, D-69120, Germany

    Miyoko Higuchi & Peter H Seeburg

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Correspondence to Kazuko Nishikura.

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Supplementary information

Supplementary Fig. 1

Differential detection of unedited and edited pri-miR-142 RNAs by the primer extension assay. (PDF 341 kb)

Supplementary Fig. 2

Detection of endogenous and recombinant ADAR and miRNA processing enzymes in transfected HEK293 cells. (PDF 465 kb)

Supplementary Fig. 3

Preparation of mammalian TSN proteins. (PDF 130 kb)

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Yang, W., Chendrimada, T., Wang, Q. et al. Modulation of microRNA processing and expression through RNA editing by ADAR deaminases. Nat Struct Mol Biol 13, 13–21 (2006). https://doi.org/10.1038/nsmb1041

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