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Review
, 125 (1), 51-63

The Dynamic Epitranscriptome: A to I Editing Modulates Genetic Information

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Review

The Dynamic Epitranscriptome: A to I Editing Modulates Genetic Information

Mansoureh Tajaddod et al. Chromosoma.

Abstract

Adenosine to inosine editing (A to I editing) is a cotranscriptional process that contributes to transcriptome complexity by deamination of adenosines to inosines. Initially, the impact of A to I editing has been described for coding targets in the nervous system. Here, A to I editing leads to recoding and changes of single amino acids since inosine is normally interpreted as guanosine by cellular machines. However, more recently, new roles for A to I editing have emerged: Editing was shown to influence splicing and is found massively in Alu elements. Moreover, A to I editing is required to modulate innate immunity. We summarize the multiple ways in which A to I editing generates transcriptome variability and highlight recent findings in the field.

Figures

Fig. 1
Fig. 1
Adenosine to inosine RNA-editing affects the transcriptome in multiple ways. Effects of A to I editing range from recoding of amino acids, consequences for alternative splicing, and links to the innate immune response. For details, please refer to the text
Fig. 2
Fig. 2
The ADAR protein family. Four different ADAR proteins have been identified in mammals. Here, the domain organization is shown. All ADAR proteins contain a deaminase domain (light blue) at the C-terminal end and a variable number of double-stranded RNA binding domains (dsRBDs, green). Z-DNA binding domains (red) are specific for ADAR1 isoforms, whereas the single-stranded RNA-binding R-domain (purple) is unique for ADAR3
Fig. 3
Fig. 3
Alu elements and their role in A to I editing. a Alu elements frequently reside in noncoding regions of genes (e.g., 3′ UTRs). If two Alu elements (depicted in blue and red) are located in inverted orientation, they can form double-stranded structures and therefore be targeted by ADAR proteins. CDS = protein coding sequence. b Alu elements may also integrate into intronic regions. As shown for the NARF pre-mRNA, two Alus form double-stranded structures and therefore are edited. Editing leads to creation of an additional 3′ splice site (3′ss) and thereby an alternative exon (AluEx) is created using an already existing 5′ splice site (5′ss)
Fig. 4
Fig. 4
Tight regulation of A to I editing and mRNA splicing at the Gria2 Q/R site. a The Q/R editing site in exon 11 (blue) forms an editing competent stem with the downstream intron 11 (gray). Two additional editing hotspots are located in the intron. Editing sites are marked by red dots. ECS = editing complementary site. b Editing at hotspots 1 and 2 has to take place in order to allow efficient removal of intron 11 by splicing. Apparently, intronic editing acts as a safe-guard to ensure efficient editing at the Q/R site in exon 11. For details, please refer to the text. Editing sites are marked by red dots. Green arrows indicate that editing enhances splicing at the 5’ss
Fig. 5
Fig. 5
A double-stranded RNA structure is required for ADAR binding. a The double-stranded structure is frequently formed between exons (first exon depicted in blue, second in red) and introns, b but can also be formed within exons. ECS = editing complementary site
Fig. 6
Fig. 6
Factors that determine or regulate adenosine to inosine editing. The level of A to I editing is determined by a series of factors: The dominant factor is the RNA structure itself. Besides this, the subcellular distribution of ADAR proteins certainly contributes to the extent of editing. Moreover, proteins have been identified that regulate editing in a site-specific manner. Finally, induction of ADAR1-p150 by interferon most likely upregulates the extent of editing
Fig. 7
Fig. 7
A to I editing and the innate immune response. The role of ADAR1 during the innate immune response is shown as proposed by Mannion and colleagues (Mannion et al. 2014). Loss of editing (for instance by mutations in ADAR1) leads to increased levels of unedited double-stranded RNA. The unedited RNA enhances the inflammatory response and acts via RIG-I or MDA5 and MAVS. Adapted from Mannion et al. (2014)

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