A-to-I RNA editing – not all events are created equal
St. Vincent’s Institute of Medical Research, Fitzroy VIC 3065, Australia.
Adenosine-to-inosine (A-to-I) editing of double-stranded RNA (dsRNA) by ADAR proteins is a highly prevalent form of RNA base modification in higher eukaryotes. Tens of thousands of A-to-I editing events are defined in the mouse, yet the functional impact of most is unknown. Inosine is interpreted as guanosine by the ribosome and other cellular machinery and therefore editing has the ability to change the amino acid sequence of encoded proteins, splice sites, the binding sites of RNA-binding proteins as well as modify the RNA secondary structure. Editing causing protein recoding is the essential function of ADAR2, but an essential role for recoding by ADAR1 has not been demonstrated. Additionally, ADAR1 has been proposed to have editing-dependent and editing-independent functions however, the relative contribution of these in vivo has not been clearly defined. A critical function of ADAR1 is editing of endogenous RNA to prevent activation of innate immune pathways via the dsRNA sensor MDA5 (Ifih1). Concurrent deletion of MDA5 rescues the embryonic lethality of Adar1 editing deficient mice (Adar1E861A/E861A). Outside of this role however, it is uncertain how ADAR1 editing contributes to normal development and homeostasis. To address this, we analysed the consequences of ADAR1 editing deficiency on murine homeostasis in the absence of MDA5. Our findings indicate that outside of the editing of MDA5-targeted self dsRNA, editing by ADAR1 is dispensable for normal murine development.