ADAR Gene Family and A-to-I RNA Editing: Diverse Roles in Posttranscriptional Gene Regulation

https://doi.org/10.1016/S0079-6603(04)79006-6Get rights and content

Publisher Summary

The biological process of A-to-I RNA editing mediated by ADAR is discussed with new directions on potentially novel targets, including the widely expressed Alu retrotransposable elements found in noncoding regions of mRNA. Many events take place after the de novo synthesis of an RNA transcript, leading to alterations from its gene-encoded origin. In addition to posttranslational modification, which occurs after the production of the polypeptide chain, RNA can be modified in several ways as to vary the amino acid sequence before it is even translated. Once transcription has commenced, the newly formed pre-mRNA must be processed by several mechanisms that operate posttranscriptionally. The RNA itself plays a role in this regulatory process by forming an assortment of secondary structures. These complex elements in part are formed by the RNA sequence itself producing double-stranded (ds) RNA, creating a configuration of bulges, stem loops, and hairpins.

Section snippets

Historical Overview

The phenomenon of RNA editing is different from splicing and polyadenylation, which are mechanisms that affect large stretches of sequence, whereas RNA editing is a site-specific alteration in order to fine-tune gene products (1). RNA editing was first discovered in trypanosome mitochondrial mRNAs, in which uridine nucleotides of its mRNA were inserted or deleted; this editing is necessary to generate functional proteins for this kinetoplastid protozoa (2). Shortly thereafter, RNA editing was

A Family of Editors

A base conversion of a ribonucleotide takes place during RNA editing. The deamination reactions of cytidine to uridine or adenosine to inosine are the best characterized examples of base modification and are the major type of RNA editing in higher eukaryotes (41). Editing via base deamination for A-to-I conversion occurs by a hydrolytic deamination reaction (Fig. 1A) (13, 42). This hydrolytic attack transpires on carbon 6 of the adenine base by removal of the exocyclic amine with oxygen serving

Requirement of Double-Stranded RNA in the A-to-I RNA Editing Mechanism

In order for the base modification reaction to occur, an ADAR protein must recognize its substrate dsRNA. Typically an mRNA forms duplex structures such as hairpins interceded by loops and bulges. This RNA topography dictates the binding and specificity of the ADAR enzymes for A-to-I editing (Fig. 5A). RNA secondary structural features consisting of hairpins containing mismatches, bulges, and loops are edited more selectively than completely base paired duplexed RNA. It appears that ADAR

In Vivo Phenotypes

The physiological consequences of ADAR A-to-I editing have been validated in various species. In a C. elegans strain containing double homozygous deletions for both c.e.ADAR1 and c.e.ADAR2 genes is viable, however, it displays defects in chemotaxis and has abnormal development of the vulva in a subset of worms lacking only c.e.ADAR1 (60). Drosophila engineered with a homozygous deletion in the lone dADAR gene are also viable but exhibit defective locomotion and behavior connected to a variety

Future Prospects

The recoding of neurotransmitter proteins by A-to-I editing appears to have a minor role for ADAR-regulating cellular events due to the low amount of editing observed as compared to other types of dsRNA substrates, although the functional consequences of neuroreceptor alterations can have a great impact on the organism as a whole. This is seen for GluR-B Q/R site editing by ADAR2, which is nearly ∼100% (97, 156). So the question arises: Why recode proteins at the RNA level? This is certainly a

Acknowledgments

This work was supported in part by grants from the National Institutes of Health, the Doris Duke Charitable Foundation, the March of Dimes, and the Commonwealth Universal Research Enhancement Program, Pennsylvania Department of Health to KN. LV is supported by NIH Postdoctoral Supplement Grant HL070045.

References (187)

  • KnightS.W. et al.

    The role of RNA editing by ADARs in RNAi

    Mol. Cell

    (2002)
  • LavorgnaG. et al.

    In search of antisense

    Trends Biochem. Sci.

    (2004)
  • MaasS. et al.

    Sequence, genomic organization and functional expression of the murine tRNA-specific adenosine deaminase ADAT1

    Gene

    (2000)
  • KellerW. et al.

    Editing of messenger RNA precursors and of tRNAs by adenosine to inosine conversion

    FEBS Lett.

    (1999)
  • BettsL. et al.

    Cytidine deaminase: The 2.3 A crystal structure of an enzyme: Transition-state analog complex

    J. Mol. Biol.

    (1994)
  • MacGinnitieA.J. et al.

    Mutagenesis of apobec-1, the catalytic subunit of the mammalian apolipoprotein B mRNA editing enzyme, reveals distinct domains that mediate cytosine nucleoside deaminase, RNA binding, and RNA editing activity

    J. Biol. Chem.

    (1995)
  • NavaratnamN. et al.

    Escherichia coli cytidine deaminase provides a molecular model for ApoB RNA editing and a mechanism for RNA substrate recognition

    J. Mol. Biol.

    (1998)
  • ChoD.S. et al.

    Requirement of dimerization for RNA editing activity of adenosine deaminases acting on RNA

    J. Biol. Chem.

    (2003)
  • SlavovD. et al.

    Comparative analysis of the RED1 and RED2 A-to-I RNA editing genes from mammals, pufferfish and zebrafish

    Gene

    (2000)
  • SlavovD. et al.

    Comparative analysis of the DRADA A-to-I RNA editing gene from mammals, pufferfish and zebrafish

    Gene

    (2000)
  • LaiF. et al.

    Mutagenic analysis of double-stranded RNA adenosine deaminase, a candidate enzyme for RNA editing of glutamate-gated ion channel transcripts

    J. Biol. Chem.

    (1995)
  • Yi-BrunozziH.Y. et al.

    Conformational changes that occur during an RNA-editing adenosine deamination reaction

    J. Biol. Chem.

    (2001)
  • HolzB. et al.

    Identification of the binding site for the extrahelical target base in N6-adenine DNA methyltransferases by photo-cross-linking with duplex oligodeoxyribonucleotides containing 5-iodouracil at the target position

    J. Biol. Chem.

    (1999)
  • GeorgeC.X. et al.

    Characterization of the 5′-flanking region of the human RNA-specific adenosine deaminase ADAR1 gene and identification of an interferon-inducible ADAR1 promoter

    Gene

    (1999)
  • KawakuboK. et al.

    Human RNA-specific adenosine deaminase (ADAR1) gene specifies transcripts that initiate from a constitutively active alternative promoter

    Gene

    (2000)
  • NieY. et al.

    Subcellular distribution of ADAR1 isoforms is synergistically determined by three nuclear discrimination signals and a regulatory motif

    J. Biol. Chem.

    (2004)
  • LiuY. et al.

    Functionally distinct double-stranded RNA-binding domains associated with alternative splice site variants of the interferon-inducible double-stranded RNA-specific adenosine deaminase

    J. Biol. Chem.

    (1997)
  • LiuY. et al.

    Editing of glutamate receptor subunit B pre-mRNA by splice-site variants of interferon-inducible double-stranded RNA-specific adenosine deaminase ADAR1

    J. Biol. Chem.

    (1999)
  • YangJ.H. et al.

    Intracellular localization of differentially regulated RNA-specific adenosine deaminase isoforms in inflammation

    J. Biol. Chem.

    (2003)
  • KawaharaY. et al.

    Regulation of glutamate receptor RNA editing and ADAR mRNA expression in developing human normal and Down's syndrome brains

    Brain Res. Dev. Brain Res.

    (2004)
  • WangQ. et al.

    Stress-induced apoptosis associated with null mutation of ADAR1 RNA editing deaminase gene

    J. Biol. Chem.

    (2004)
  • HartnerJ.C. et al.

    Liver disintegration in the mouse embryo caused by deficiency in the RNA-editing enzyme ADAR1

    J. Biol. Chem.

    (2004)
  • LehmannK.A. et al.

    The importance of internal loops within RNA substrates of ADAR1

    J. Mol. Biol.

    (1999)
  • GottJ.M. et al.

    Functions and mechanisms of RNA editing

    Annu. Rev. Genet.

    (2000)
  • ChenS.H. et al.

    Apolipoprotein B-48 is the product of a messenger RNA with an organ-specific in-frame stop codon

    Science

    (1987)
  • TengB. et al.

    Molecular cloning of an apolipoprotein B messenger RNA editing protein

    Science

    (1993)
  • BassB.L.

    RNA editing by adenosine deaminases that act on RNA

    Annu. Rev. Biochem.

    (2002)
  • KimU. et al.

    Molecular cloning of cDNA for double-stranded RNA adenosine deaminase, a candidate enzyme for nuclear RNA editing

    Proc. Natl. Acad. Sci. USA

    (1994)
  • WagnerR.W. et al.

    A double-stranded RNA unwinding activity introduces structural alterations by means of adenosine to inosine conversions in mammalian cells and Xenopus eggs

    Proc. Natl. Acad. Sci. USA

    (1989)
  • O'ConnellM.A. et al.

    Cloning of cDNAs encoding mammalian double-stranded RNA-specific adenosine deaminase

    Mol. Cell. Biol.

    (1995)
  • MelcherT. et al.

    A mammalian RNA editing enzyme

    Nature

    (1996)
  • LaiF. et al.

    Editing of glutamate receptor B subunit ion channel RNAs by four alternatively spliced DRADA2 double-stranded RNA adenosine deaminases

    Mol. Cell. Biol.

    (1997)
  • GerberA. et al.

    Two forms of human double-stranded RNA-specific editase 1 (hRED1) generated by the insertion of an Alu cassette

    RNA

    (1997)
  • ChenC.X. et al.

    A third member of the RNA-specific adenosine deaminase gene family, ADAR3, contains both single- and double-stranded RNA binding domains

    RNA

    (2000)
  • BassB.L. et al.

    A standardized nomenclature for adenosine deaminases that act on RNA

    RNA

    (1997)
  • PaulM.S. et al.

    Inosine exists in mRNA at tissue-specific levels and is most abundant in brain mRNA

    EMBO J.

    (1998)
  • HoopengardnerB. et al.

    Nervous system targets of RNA editing identified by comparative genomics

    Science

    (2003)
  • MorseD.P. et al.

    RNA hairpins in noncoding regions of human brain and Caenorhabditis elegans mRNA are edited by adenosine deaminases that act on RNA

    Proc. Natl. Acad. Sci. USA

    (2002)
  • RueterS.M. et al.

    Regulation of alternative splicing by RNA editing

    Nature

    (1999)
  • MorseD.P. et al.

    Long RNA hairpins that contain inosine are present in Caenorhabditis elegans poly(A)+ RNA

    Proc. Natl. Acad. Sci. USA

    (1999)
  • Cited by (147)

    • Regulation of non-coding RNAs

      2023, Navigating Non-coding RNA: From Biogenesis to Therapeutic Application
    • Inosine and its methyl derivatives: Occurrence, biogenesis, and function in RNA

      2022, Progress in Biophysics and Molecular Biology
      Citation Excerpt :

      Likewise, editing of 5′ AU dinucleotide leads to the formation of IU which can act as 5′ GU splice site recognition sequence (reviewed in Nishikura, 2010). A-to-I editing of a 3′ splice site AG forms IG which is recognized as 3′GG and hence leads to the destruction of this splice site (Valente and Nishikura, 2005). The RNA-induced silencing complex (RISC) subunit Tudor-SN has been reported to specifically recognize hyperedited dsRNA substrates containing multiple I·U and U·I wobble base pairs and promote the cleavage of such dsRNA substrates (Scadden, 2005).

    • The adaptive potential of RNA editing-mediated miRNA-retargeting in cancer

      2019, Biochimica et Biophysica Acta - Gene Regulatory Mechanisms
    View all citing articles on Scopus
    View full text