Background In 1979, the first ever DNA crystal that was solved led to the surprising discovery of the left-hand Z-DNA conformation This structure forms from the right-handed classical B-DNA by flipping the bases over. The first protein shown to bind Z-DNA with high affinity was the double-stranded RNA editing protein ADAR1, but exactly why was uncertain for many years. A Proline to Alanine substitution at position 193 of ADAR1 (P193A) and an Asparagine to Serine substitution at position 173 (N173S), both in the Zα domain have been reported in families with Aicardi Goutières Syndrome type 6 , but also in the general population. Aicardi Goutières Syndrome causes severe neurological disease marked by dystonia with very few individuals surviving childhood. Disease is associated with a type I interferon signature.

Materials and Methods Structural and Genetic Analysis of ADAR1 biology

Results Evidence that P193A and N173S variants of the Z-RNA binding domain, Zα, of the RNA editing enzyme ADAR1 are causal for the Type I Interferonopathy Aicardi Goutières syndrome will be presented. The disease outcomes are driven by double-stranded RNAs derived from endogenous Alu inverted repeat retrotransposons. The Alu elements contain a Z-box with Z-RNA forming sequences that are normally bound by the Zα domain of ADAR1 to prevent activation of the double-stranded RNA sensor to MDA5 that drives the interferon response. The Alu elements mark host-transcripts as self, preventing auto-reactivity.

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Abstract 1505 Figure 1

Double-stranded A-RNA (dsRNA) formed by Alu RNA elements is twisted and shortened as the helicase MDA5 engages it. If the right-handed dsRNA (helical length =2.46 nm) contains a Z-Box, then the tension generated is relieved by flipping the sequence to the longer left-handed Z-RNA conformation (helical length = 4.56 nm). The flip causes the immune proteins to fall off the RNA. The Z-RNA formed engages the editing enzyme ADAR1. ADAR1 modifies dsRNA, producing single-stranded RNA that does not cause immune activation. The Z-Box sequences are called flipons.

Conclusions The regulation of type I Interferon responses by Z-RNA is the first time that a biological role for flipons has been conclusively confirmed. The P193A variant (rs145588689) is present in 0.2% of the world population and in 0.3~04% of non-Finnish Europeans. It seems likely that the variant underwent selection during the period of urbanization during the Middle Ages. The increased interferon responses may have enhanced survival against pandemic viruses. Whether P193A increases risk of systemic lupus erythematosus is unknown.