ADAR-Deficient Mice Exhibit Complex Tissue-Specific Splicing Patterns

Adenosine deamination-type RNA editing and pre-mRNA splicing are both co-transcriptional processes. Adenosine deaminases acting on RNA (ADARs) recognize double-stranded structures, typically formed between adjacent complementary sequences within one RNA. Frequently, editing events that lead to the recoding of messenger RNAs (mRNAs) are defined by base pairing between the exonic editing site with an adjacent intronic editing complementary sequence (ECS). Consequently, editing needs to occur before the ECS is removed by splicing, implying that the speed of splicing affects the extent of editing. Conversely, it has been shown that inhibition of editing can interfere with splicing. In this study, using genetic mouse models in which either one of the two catalytically active editing enzymes ADAR1 or ADAR2 are deleted we determine their impact on pre-mRNA splicing. We show that lack of ADAR1 strongly affects splicing while loss of ADAR2 only has a minor impact on splicing. We also show that impact of ADAR1 on splicing differs in different tissues and can be both editing-dependent as well as independent. We also show that A-to-I RNA editing reduces splice rates and this interplay can impact protein levels. Finally, we show that RNA editing can impact binding motifs of RNA binding proteins involved in splicing.