RNA editing catalyzed by ADAR1 and its function in mammalian cells

In mammalian cells two active enzymes, ADAR1 and ADAR2, carry out A-to-I RNA editing. These two editases share many common features in their protein structures, catalytic activities, and substrate requirements. However, the phenotypes of the knockout animals are remarkably different, which indicate the distinct functions they play. The most striking effect of ADAR1 knockout is cell death and interruption of embryonic development that are not observed in ADAR2 knockout. Evidences have shown that ADAR1 plays critical roles in the differentiating cells in embryo and adult tissues to support the cell's survival and permit their further differentiation and maturation. However, our knowledge in understanding of the mechanism by which ADAR1 exerts its unique effects is very limited. Many efforts had been made trying to understand why ADAR1 is so important that it is indispensible for animal survival, including studies that identify the RNA editing substrates and studies on non-editing mechanisms. The interest of this review is focused on the question why ADAR1 and not ADAR2 is required for cell survival. Therefore, only the data, published and unpublished, potentially connecting ADAR1 to its cell death effect is selectively cited and discussed here. The features of cell death caused by ADAR1 deletion are summarized. Potential involvement of interferon and protein kinase RNA-activated (PKR) pathways is proposed, but obviously more experimental evaluations are needed.