Fig. 1: ADAR1 regulates immune response and senescence through A-to-I RNA editing dependent and independent pathways, respectively.

a Mutation of the ADAR1 Zα domain or ADAR1 depletion causes deficiency in A-to-I RNA editing, leading to the accumulation of Z-RNA. The accumulated Z-RNA subsequently activates ZBP1 to drive autoimmune diseases by inducing necroptosis or apoptosis in ADAR1-deficient cells. In contrast, ADAR1 tends to be overexpressed in cancer. The elevated expression of ADAR1 will reduce Z-RNA accumulation through A-to-I RNA editing, thereby inhibiting ZBP1 activation and ZBP1-mediated programmed necrosis of cells. Considering the similarity between Z-DNA and Z-RNA in structure, Zhang et al. screened a small molecule, CBL0137, that can transform a large amount of B-DNA into Z-DNA for activating ZBP1 to enhance immunotherapy. b In aging cells, ADAR1 is downregulated by the lysosomal-mediated autophagy pathway, which decreases the association between HuR and SIRT1 mRNA, leading to the significantly reduced stability of SIRT1 mRNA. The reduced expression of SIRT1 will further promote the association of EIF3a with p16^INK4a mRNA to accelerate its translation. This A-to-I independent pathway appears to be a mast regulator of cell senescence through modulating p16^INK4a levels