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Chapter 19 : Adenosine-to-Inosine Conversion in mRNA

Authors: Susan M. Rueter1, Ronald B. Emeson1
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Affiliations: 1: Department of Pharmacology, Vanderbilt University, 460 Medical Research Building 2, Nashville, Tennessee 37232-6600
Content Type: Monograph
Publication Year: 1998

Category: Microbial Genetics and Molecular Biology

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Abstract:

The conversion of adenosine to inosine (A-to-I) by RNA editing, at specific positions within RNAs, represents an increasingly common posttranscriptional modification for generating diversity and flexibility in eukaryotic gene expression. This chapter describes a number of mRNA substrates that undergo A-to-I editing events, the effects that such alterations in coding potential have upon protein function, and the candidate enzymes responsible for such posttranscriptional modifications. While nucleotide sequence analyses have revealed the presence of a CGG codon encoding the critical regulatory arginine residue within the TM2 region of GluR-B cDNAs, a glutamine (CAG) codon was found in GluR-B genomic DNA at this position Q/R site. The editing of RNAs encoding glutamate receptor subunits results from the conversion of genomically encoded adenosine residues to the guanosine-like nucleotides found in cDNAs generated from mature GluR mRNA transcripts. The hepatitis delta virus (HDV) is a subviral human pathogen whose packaging and propagation are dependent on concurrent infection with the hepatitis B virus. Recent studies of RNA editing in polyomavirus have suggested that this posttranscriptional modification represents a mechanism by which RNA transcripts expressed early after viral infection are inactivated subsequent to viral DNA replication (the late phase). While future work will further define the cellular and molecular basis for dsRNA adenosine deamination, the functional consequences of subtle A-to-I changes in mRNAs and the alterations in amino acid sequence for resultant proteins are bound to be profound.

Citation: Rueter S, Emeson R. 1998. Adenosine-to-Inosine Conversion in mRNA, p 343-361. In Grosjean H, Benne R (ed), Modification and Editing of RNA. ASM Press, Washington, DC. doi: 10.1128/9781555818296.ch19

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Adenosine-to-Inosine Conversion in mRNA
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Citation: Rueter S, Emeson R. 1998. Adenosine-to-Inosine Conversion in mRNA, p 343-361. In Grosjean H, Benne R (ed), Modification and Editing of RNA. ASM Press, Washington, DC. doi: 10.1128/9781555818296.ch19
/content/10.1128/9781555818296.chap19.fig19-1
Figure 1

A-to-I editing events in transcripts encoding non-NMDA glutamatc receptor subunits. A schematic representation of the predicted topology for GluR-A is presented indicating the relative positions of amino acid alterations produced as a result of A-to-I editing events and the location of the flip/flop domain (black rectangle); the topology of subunits other than GluR-A ( ) has not been determined. The posttranscriptional conversion of adenosine to inosine can be seen as an A-to-G discrepancy between the nucleotide sequences of genomic and complementary DNA (cDNA). The genomic (upper), cDNA (lower) and predicted amino acid alterations resulting from these editing events are presented.

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Figure 1

A-to-I editing events in transcripts encoding non-NMDA glutamatc receptor subunits. A schematic representation of the predicted topology for GluR-A is presented indicating the relative positions of amino acid alterations produced as a result of A-to-I editing events and the location of the flip/flop domain (black rectangle); the topology of subunits other than GluR-A ( ) has not been determined. The posttranscriptional conversion of adenosine to inosine can be seen as an A-to-G discrepancy between the nucleotide sequences of genomic and complementary DNA (cDNA). The genomic (upper), cDNA (lower) and predicted amino acid alterations resulting from these editing events are presented.

Citation: Rueter S, Emeson R. 1998. Adenosine-to-Inosine Conversion in mRNA, p 343-361. In Grosjean H, Benne R (ed), Modification and Editing of RNA. ASM Press, Washington, DC. doi: 10.1128/9781555818296.ch19
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Figure 2

Predicted secondary structure of pre-mRNA transcripts encoding non-NMDA receptor subunits (GluR-B, GluR-5, and GluR-6), the 2C subtype of serotonin receptor (5-HTR) and the hepatitis delta virus (HDV) antigenome in the regions of major editing modifications using an RNA folding algorithm (RNAFOLD; Scientific & Educational Software). The positions of edited nucleotides are indicated by open circles, intron-exon boundaries are designated, and nucleotides omitted from the figure are indicated in the loops. Nucleotide coordinates are relative to the Q/R, R/G or A editing sites.

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Figure 2

Predicted secondary structure of pre-mRNA transcripts encoding non-NMDA receptor subunits (GluR-B, GluR-5, and GluR-6), the 2C subtype of serotonin receptor (5-HTR) and the hepatitis delta virus (HDV) antigenome in the regions of major editing modifications using an RNA folding algorithm (RNAFOLD; Scientific & Educational Software). The positions of edited nucleotides are indicated by open circles, intron-exon boundaries are designated, and nucleotides omitted from the figure are indicated in the loops. Nucleotide coordinates are relative to the Q/R, R/G or A editing sites.

Citation: Rueter S, Emeson R. 1998. Adenosine-to-Inosine Conversion in mRNA, p 343-361. In Grosjean H, Benne R (ed), Modification and Editing of RNA. ASM Press, Washington, DC. doi: 10.1128/9781555818296.ch19
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Figure 3

Experimental strategy for determining the identity of a modified nucleotide(s) subsequent to RNA editing. A biochemical strategy is presented in which an RNA substrate uniformly labeled with [-P]-ATP is subjected to in vitro editing using HeLa cell nuclear extract as a source of enzymatic activity. The resulting in vitro reaction product is digested to completion with nuclease P1, yielding nucleotide 5′-monophosphates that can be resolved by thin-layer chromatography.

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Image of Figure 3
Figure 3

Experimental strategy for determining the identity of a modified nucleotide(s) subsequent to RNA editing. A biochemical strategy is presented in which an RNA substrate uniformly labeled with [-P]-ATP is subjected to in vitro editing using HeLa cell nuclear extract as a source of enzymatic activity. The resulting in vitro reaction product is digested to completion with nuclease P1, yielding nucleotide 5′-monophosphates that can be resolved by thin-layer chromatography.

Citation: Rueter S, Emeson R. 1998. Adenosine-to-Inosine Conversion in mRNA, p 343-361. In Grosjean H, Benne R (ed), Modification and Editing of RNA. ASM Press, Washington, DC. doi: 10.1128/9781555818296.ch19
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Figure 4

RNA editing of 5-HTR transcripts. (A) Nucleotide and predicted amino acid sequence alignments between 5-HTR genomic and cDNA sequences; A-to-G nucleotide discrepancies and predicted alterations in amino acid sequence are indicated in inverse and underlined lettering, respectively. (B) A schematic representation of the predicted topology for the 5-HT receptor is presented, indicating the sites of amino acid alteration within the second intracellular loop resulting from RNA editing events. The amino acid sequence of the 5-HTR is indicated with the one-letter amino acid code ( ).

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Figure 4

RNA editing of 5-HTR transcripts. (A) Nucleotide and predicted amino acid sequence alignments between 5-HTR genomic and cDNA sequences; A-to-G nucleotide discrepancies and predicted alterations in amino acid sequence are indicated in inverse and underlined lettering, respectively. (B) A schematic representation of the predicted topology for the 5-HT receptor is presented, indicating the sites of amino acid alteration within the second intracellular loop resulting from RNA editing events. The amino acid sequence of the 5-HTR is indicated with the one-letter amino acid code ( ).

Citation: Rueter S, Emeson R. 1998. Adenosine-to-Inosine Conversion in mRNA, p 343-361. In Grosjean H, Benne R (ed), Modification and Editing of RNA. ASM Press, Washington, DC. doi: 10.1128/9781555818296.ch19
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Figure 5

Alternatively spliced variants of human ADAR1 and ADAR2 mRNA produce multiple protein isoforms. Schematic representations of ADAR1 (A) and ADAR2 (B) protein isoforms are presented, indicating the locations of the putative nuclear localization signal (NLS; vertical stripe), Z-DNA binding domain (Z; black), dsRNA-binding domains (gray) and the adenosine deaminase domain (angled stripe). The location of zinc-coordination residues within the deaminase domain are designated by asterisks and the amino acid coordinates for each domain, relative to the amino terminus, are indicated. The specific amino acid residues deleted in the ADAR1b and ADAR1c isoforms or inserted in the deaminase domain of the ADAR2b and ADAR2c isoforms (Crosshatch) are indicated, as well as the amino acid residues present in unique ADAR2 carboxyl termini (black) with the one-letter amino acid code.

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Figure 5

Alternatively spliced variants of human ADAR1 and ADAR2 mRNA produce multiple protein isoforms. Schematic representations of ADAR1 (A) and ADAR2 (B) protein isoforms are presented, indicating the locations of the putative nuclear localization signal (NLS; vertical stripe), Z-DNA binding domain (Z; black), dsRNA-binding domains (gray) and the adenosine deaminase domain (angled stripe). The location of zinc-coordination residues within the deaminase domain are designated by asterisks and the amino acid coordinates for each domain, relative to the amino terminus, are indicated. The specific amino acid residues deleted in the ADAR1b and ADAR1c isoforms or inserted in the deaminase domain of the ADAR2b and ADAR2c isoforms (Crosshatch) are indicated, as well as the amino acid residues present in unique ADAR2 carboxyl termini (black) with the one-letter amino acid code.

Citation: Rueter S, Emeson R. 1998. Adenosine-to-Inosine Conversion in mRNA, p 343-361. In Grosjean H, Benne R (ed), Modification and Editing of RNA. ASM Press, Washington, DC. doi: 10.1128/9781555818296.ch19
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