Abstract 2084 Going from right-handed RNA to left-handed Z-RNA: Gotta unfold first!

Z-RNA is a left-handed double helix first discovered in vitro several decades ago and subsequently shown to exist in vivo. However, its biological significance remained a mystery. Z-RNA has recently regained interest as several laboratories have shown that mutations altering the ability of proteins to recognize Z-RNA were accompanied with hyper-inflammatory phenotypes. Such proteins contain a Z-binding domain called Zα and include ADAR1 (Adenosine Deaminase Acting on RNA 1). Zα domains stabilize the higher-energy conformation of Z-RNA by making specific interactions with its unique geometry. However, the mechanism by which RNA contorts from right- to left-handed conformations in the presence of Zα domains is not well understood. Here, we used biophysical approaches to determine that nucleic acid duplexes in the right-handedness melt before adopting the left-handedness. We correlate the ease of melting a nucleic acid duplex to Z-form adoption rates in presence of Zα. Our previous work showed that the Zα domain of ADAR1 binds to various RNA fragments from Alu elements found in mRNAs, and our current results provide critical insights into finding potential Z-adopting regions in host and viral RNAs. National Science Foundation (Award #2153787 to Q.V. and B.V.) National Institutes of Health (Award #1F31AI167396 to P.N.