Reverse transcriptase incorporates guanosines (G) and thymidines (T) into cDNA at positions where inosines and uridines are present in the RNA, leading to base changes not present in the genomic DNA. These edits are the result of the deamination activity by proteins belonging to the adenosine deaminase acting on RNA (ADAR) ( Bass, 2002 Nishikura, 2010 Savva et al., 2012) and the apolipoprotein B mRNA editing enzyme catalytic subunit (APOBEC) ( Blanc and Davidson, 2010 Sharma et al., 2015, 2019 Lerner et al., 2018 Pecori et al., 2022) families, respectively. In mammals, two distinct kinds of RNA editing have been described so far, adenosine to inosine (A-to-I) and cytidine to uridine (C-to-U). For example, RNA editing is a mechanism that alters the RNA sequence itself. Once compared to genomic data (DNA-seq), RNA-seq reveals information about several post-transcriptional processes that RNA molecules can undergo. Recent years have seen an exponential increase in RNA sequencing (RNA-seq) technologies providing scientists with an incredible amount of transcriptomic data. Our findings, also confirmed by deep transcriptome data, demonstrate that such loci can be recognized simply through the presence of A-to-I and U-to-C mismatches within the same locus, reflective A-to-I editing both in the sense-oriented transcript and in the cis-natural antisense transcript (cis-NAT), implying that such clusters could be a mark of functionally relevant ADAR1 editing events.
Such editing events, occurring on overlapping genes transcribed in opposite directions, have recently been demonstrated to be immunogenic and have been linked with autoimmune and immune-related diseases. A more in-depth analysis revealed that putative U-to-C edits result from A-to-I editing on overlapping antisense RNAs that are transcribed from the same loci. The same findings were also observed for the human long intergenic non-coding RNA p21 (hLincRNA-p21). These U-to-C edits were present in several cell lines and appeared regulated in response to specific environmental stimuli. During one of these validations on DDX58 mRNA, along with A-to-I RNA editing sites, we encountered putative U-to-C editing. These methods are powerful but not error-free, making routine validation of newly-described editing sites necessary. Recent improvements in RNA sequencing technologies have led to the discovery of a continuously growing number of editing sites.
In mammals, two kinds of RNA editing have been described so far, adenosine to inosine (A-to-I) and cytidine to uridine (C-to-U) editing.
1Division of Immune Diversity, German Cancer Research Centre (DKFZ), Research Program Immunology and Cancer, Heidelberg, Germany.Riccardo Pecori 1,2* Isabel Chillón 3 † Claudio Lo Giudice 4 Annette Arnold 1 Sandra Wüst 5 Marco Binder 5 Marco Marcia 3 Ernesto Picardi 4 Fotini Nina Papavasiliou 1*
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