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Review
. 2015 Sep 30;5(4):2338-62.
doi: 10.3390/biom5042338.

New Insights into the Biological Role of Mammalian ADARs; the RNA Editing Proteins

Niamh Mannion  1 , Fabiana Arieti  2 , Angela Gallo  3 , Liam P Keegan  4 , Mary A O'Connell  5
Affiliations
Review

New Insights into the Biological Role of Mammalian ADARs; the RNA Editing Proteins

Niamh Mannion et al. Biomolecules. .

Abstract

The ADAR proteins deaminate adenosine to inosine in double-stranded RNA which is one of the most abundant modifications present in mammalian RNA. Inosine can have a profound effect on the RNAs that are edited, not only changing the base-pairing properties, but can also result in recoding, as inosine behaves as if it were guanosine. In mammals there are three ADAR proteins and two ADAR-related proteins (ADAD) expressed. All have a very similar modular structure; however, both their expression and biological function differ significantly. Only two of the ADAR proteins have enzymatic activity. However, both ADAR and ADAD proteins possess the ability to bind double-strand RNA. Mutations in ADARs have been associated with many diseases ranging from cancer, innate immunity to neurological disorders. Here, we will discuss in detail the domain structure of mammalian ADARs, the effects of RNA editing, and the role of ADARs in human diseases.

Keywords: ADAR; Alu elements; RNA editing; cancer; deaminase domain; dsRBDs.

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Figures

Figure 1
Figure 1
Domain organization of ADAR and ADAD proteins expressed in Homo sapiens. All of the proteins contain N-terminal dsRBDs and C-terminal deaminase domains. An arginine rich (R) region is present at the N-terminus of ADAR3. There are two isoforms of hADAR1, ADAR1 p110 and ADAR1p150, both of which contain a Z-DNA binding domains (ZBD) at the N-terminal.
Figure 2
Figure 2
Structural information of ADAR enzymes. (A) NMR structure of the dsRBD1 and dsRBD2 of hADAR2 (blue) in complex with the RG stem loop RNA target [37]. The specific adenosine that is deaminated in the catalytic reaction is highlighted in red. In grey is shown where the deaminase domain is likely positioning during the reaction. PDB file: 2L3J. (B) Crystal structure of the catalytic domain of hADAR2 [41], secondary structures are colored from yellow (N-terminus) to red (C-terminus). The Zinc ion and inositol hexakisphosphate molecule (IP6) cofactor are highlighted and colored in blue. PDB file: 1ZY7.
Figure 3
Figure 3
Intracellular detection of viral RNA by PRRs and activation of the innate immune response. The three classes of PRRs responsible for detection of viral RNA are the TLRs, the RLRs, and the NLRs. In the endosome viral ssRNA is detected by TLR7 whereas viral dsRNA is recognized by TLR3. TLR7 recruits the signaling adaptor MyD88 whereas TLR3 associates TRIF. MyD88 elicits the production of type I IFNs through the direct activation of IRF7. TRIF activates the TRAF family member-associated TANK and IKKε both of which undergo phosphorylation to activate both IRF3 and IRF7. Both IRF3 and IRF7 form homodimers which translocate to the nucleus leading to the induction of type I IFN. At the same time, both TRIF and MyD88 activate IKK. The IKK complex triggers the release and translocation of NF-κB to the nucleus leading to the production of pro-inflammatory cytokines. In the cytoplasm, short dsRNA with 5'triphospahte ends is detected by RIG-I and long dsRNA is sensed by MDA5. Activation of RIG-I and MDA5 results in the recruitment of MAVS via CARD domain interactions. MAVS dependent signaling causes the translocation of the transcription factors IRF3 and NF-κB for the induction of type I IFN and pro-inflammatory cytokines respectively. The inflammasome is activated by dsRNA via NALP3-dependent signaling pathway. NALP3 together with ASC recruit pro-caspase-1 which in turn undergoes auto-cleavage to produce caspase-1. Activation of caspase-1 is required for the cleavage of pro-IL-1β and pro-IL-18, and subsequent secretion of the proinflammatory cytokines IL-1β and IL-18, respectively. ADAR1p150 edits dsRNA within the cytoplasm and is induced by IFN.
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References

    1. Machnicka M.A., Milanowska K., Osman Oglou O., Purta E., Kurkowska M., Olchowik A., Januszewski W., Kalinowski S., Dunin-Horkawicz S., Rother K.M., et al. Modomics: A database of RNA modification pathways—2013 update. Nucleic Acids Res. 2013;41:D262–D267. doi: 10.1093/nar/gks1007. - DOI - PMC - PubMed
    1. Benne R., van den Burg J., Brakenhoff J., Sloof P., van Boom J.H., Tromp M.C. Major transcript of the frameshifted coxii gene from trypanosome mitochondria contains four nucleotides that are not encoded in the DNA. Cell. 1986;46:819–826. doi: 10.1016/0092-8674(86)90063-2. - DOI - PubMed
    1. Stuart K.D., Schnaufer A., Ernst N.L., Panigrahi A.K. Complex management: RNA editing in trypanosomes. Trends Biochem. Sci. 2005;30:97–105. doi: 10.1016/j.tibs.2004.12.006. - DOI - PubMed
    1. Rebagliati M.R., Melton D.A. Antisense RNA injections in fertilized frog eggs reveal an RNA duplex unwinding activity. Cell. 1987;48:599–605. doi: 10.1016/0092-8674(87)90238-8. - DOI - PubMed
    1. Bass B.L., Weintraub H. A developmental regulated activity that unwinds RNA duplexes. Cell. 1987;48:607–613. doi: 10.1016/0092-8674(87)90239-X. - DOI - PubMed

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