ADAR1 Forms a Complex with Dicer to Promote MicroRNA Processing and RNA-induced Gene Silencing

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2013 Apr 30

PMID 23622242

Citations 211

Authors

Hiromitsu Ota

Masayuki Sakurai

Ravi Gupta

Louis Valente

Bjorn-Erik Wulff

Kentaro Ariyoshi

Hisashi Iizasa

Ramana V Davuluri

Kazuko Nishikura

Affiliations

Soon will be listed here.

Abstract

Adenosine deaminases acting on RNA (ADARs) are involved in RNA editing that converts adenosine residues to inosine specifically in double-stranded RNAs. In this study, we investigated the interaction of the RNA editing mechanism with the RNA interference (RNAi) machinery and found that ADAR1 forms a complex with Dicer through direct protein-protein interaction. Most importantly, ADAR1 increases the maximum rate (Vmax) of pre-microRNA (miRNA) cleavage by Dicer and facilitates loading of miRNA onto RNA-induced silencing complexes, identifying a new role of ADAR1 in miRNA processing and RNAi mechanisms. ADAR1 differentiates its functions in RNA editing and RNAi by the formation of either ADAR1/ADAR1 homodimer or Dicer/ADAR1 heterodimer complexes, respectively. As expected, the expression of miRNAs is globally inhibited in ADAR1(-/-) mouse embryos, which, in turn, alters the expression of their target genes and might contribute to their embryonic lethal phenotype.

Citing Articles

Conformational reorganization and phase separation drive hyper-editing of ADR-2-ADBP-1 complex.

Mu J, Wu C, Xu K, Liu X, Fu Y, Zhang Z Nucleic Acids Res. 2025; 53(5).

PMID: 40037706 PMC: 11879458. DOI: 10.1093/nar/gkaf148.

ADAR1 Promotes the Progression and Temozolomide Resistance of Glioma Through p62-Mediated Selective Autophagy.

Zhang Y, Guo H, Bu J, Wang W, Wang L, Liu Z CNS Neurosci Ther. 2025; 31(1):e70168.

PMID: 39825637 PMC: 11742087. DOI: 10.1111/cns.70168.

The biogenesis and regulation of animal microRNAs.

Kim H, Lee Y, Kim V Nat Rev Mol Cell Biol. 2024; .

PMID: 39702526 DOI: 10.1038/s41580-024-00805-0.

Dimerization of ADAR1 modulates site-specificity of RNA editing.

Mboukou A, Rajendra V, Messmer S, Mandl T, Catala M, Tisne C Nat Commun. 2024; 15(1):10051.

PMID: 39572551 PMC: 11582362. DOI: 10.1038/s41467-024-53777-2.

ADAR1 enhances tumor proliferation and radioresistance in non-small cell lung cancer by interacting with Rad18.

Tian C, Li C, Wang J, Liu Y, Gao J, Hong X Cell Oncol (Dordr). 2024; .

PMID: 39570561 DOI: 10.1007/s13402-024-01012-x.

References

Nishikura K . Functions and regulation of RNA editing by ADAR deaminases. Annu Rev Biochem. 2010; 79:321-49. PMC: 2953425. DOI: 10.1146/annurev-biochem-060208-105251. View

Nasser M, Datta J, Nuovo G, Kutay H, Motiwala T, Majumder S . Down-regulation of micro-RNA-1 (miR-1) in lung cancer. Suppression of tumorigenic property of lung cancer cells and their sensitization to doxorubicin-induced apoptosis by miR-1. J Biol Chem. 2008; 283(48):33394-405. PMC: 2586284. DOI: 10.1074/jbc.M804788200. View

Kawahara Y, Zinshteyn B, Chendrimada T, Shiekhattar R, Nishikura K . RNA editing of the microRNA-151 precursor blocks cleavage by the Dicer-TRBP complex. EMBO Rep. 2007; 8(8):763-9. PMC: 1978079. DOI: 10.1038/sj.embor.7401011. View

Wang Q, Miyakoda M, Yang W, Khillan J, Stachura D, Weiss M . Stress-induced apoptosis associated with null mutation of ADAR1 RNA editing deaminase gene. J Biol Chem. 2003; 279(6):4952-61. DOI: 10.1074/jbc.M310162200. View

Hartner J, Walkley C, Lu J, Orkin S . ADAR1 is essential for the maintenance of hematopoiesis and suppression of interferon signaling. Nat Immunol. 2008; 10(1):109-15. PMC: 2701568. DOI: 10.1038/ni.1680. View

Cho D, Yang W, Lee J, Shiekhattar R, Murray J, Nishikura K . Requirement of dimerization for RNA editing activity of adenosine deaminases acting on RNA. J Biol Chem. 2003; 278(19):17093-102. DOI: 10.1074/jbc.M213127200. View

Kawahara Y, Megraw M, Kreider E, Iizasa H, Valente L, Hatzigeorgiou A . Frequency and fate of microRNA editing in human brain. Nucleic Acids Res. 2008; 36(16):5270-80. PMC: 2532740. DOI: 10.1093/nar/gkn479. View

Lee Y, Hur I, Park S, Kim Y, Suh M, Kim V . The role of PACT in the RNA silencing pathway. EMBO J. 2006; 25(3):522-32. PMC: 1383527. DOI: 10.1038/sj.emboj.7600942. View

Scadden A . The RISC subunit Tudor-SN binds to hyper-edited double-stranded RNA and promotes its cleavage. Nat Struct Mol Biol. 2005; 12(6):489-96. DOI: 10.1038/nsmb936. View

10.

Ma E, MacRae I, Kirsch J, Doudna J . Autoinhibition of human dicer by its internal helicase domain. J Mol Biol. 2008; 380(1):237-43. PMC: 2927216. DOI: 10.1016/j.jmb.2008.05.005. View

11.

Nishikura K . Editor meets silencer: crosstalk between RNA editing and RNA interference. Nat Rev Mol Cell Biol. 2006; 7(12):919-31. PMC: 2953463. DOI: 10.1038/nrm2061. View

12.

Liu J, Carmell M, Rivas F, Marsden C, Thomson J, Song J . Argonaute2 is the catalytic engine of mammalian RNAi. Science. 2004; 305(5689):1437-41. DOI: 10.1126/science.1102513. View

13.

Fritz J, Strehblow A, Taschner A, Schopoff S, Pasierbek P, Jantsch M . RNA-regulated interaction of transportin-1 and exportin-5 with the double-stranded RNA-binding domain regulates nucleocytoplasmic shuttling of ADAR1. Mol Cell Biol. 2009; 29(6):1487-97. PMC: 2648229. DOI: 10.1128/MCB.01519-08. View

14.

Meister G, Landthaler M, Patkaniowska A, Dorsett Y, Teng G, Tuschl T . Human Argonaute2 mediates RNA cleavage targeted by miRNAs and siRNAs. Mol Cell. 2004; 15(2):185-97. DOI: 10.1016/j.molcel.2004.07.007. View

15.

Yang W, Chendrimada T, Wang Q, Higuchi M, Seeburg P, Shiekhattar R . Modulation of microRNA processing and expression through RNA editing by ADAR deaminases. Nat Struct Mol Biol. 2005; 13(1):13-21. PMC: 2950615. DOI: 10.1038/nsmb1041. View

16.

Hartner J, Schmittwolf C, Kispert A, Muller A, Higuchi M, Seeburg P . Liver disintegration in the mouse embryo caused by deficiency in the RNA-editing enzyme ADAR1. J Biol Chem. 2003; 279(6):4894-902. DOI: 10.1074/jbc.M311347200. View

17.

Zhao Y, Ransom J, Li A, Vedantham V, von Drehle M, Muth A . Dysregulation of cardiogenesis, cardiac conduction, and cell cycle in mice lacking miRNA-1-2. Cell. 2007; 129(2):303-17. DOI: 10.1016/j.cell.2007.03.030. View

18.

Dlakic M . DUF283 domain of Dicer proteins has a double-stranded RNA-binding fold. Bioinformatics. 2006; 22(22):2711-4. DOI: 10.1093/bioinformatics/btl468. View

19.

Koscianska E, Starega-Roslan J, Krzyzosiak W . The role of Dicer protein partners in the processing of microRNA precursors. PLoS One. 2011; 6(12):e28548. PMC: 3232248. DOI: 10.1371/journal.pone.0028548. View

20.

Landthaler M, Gaidatzis D, Rothballer A, Chen P, Soll S, Dinic L . Molecular characterization of human Argonaute-containing ribonucleoprotein complexes and their bound target mRNAs. RNA. 2008; 14(12):2580-96. PMC: 2590962. DOI: 10.1261/rna.1351608. View