Z-RNA biology: a central role in the innate immune response?

Abstract

Z-RNA is a higher-energy, left-handed conformation of RNA, whose function has remained elusive. A growing body of work alludes to regulatory roles for Z-RNA in the immune response. Here, we review how Z-RNA features present in cellular RNAs —especially containing retroelements— could be recognized by a family of winged helix proteins, with an impact on host defense. We also discuss how mutations to specific Z-contacting amino acids disrupt their ability to stabilize Z-RNA, resulting in functional losses. We end by highlighting knowledge gaps in the field, which, if addressed, would significantly advance this active area of research.

Structure and Formation of Z-DNA and Z-RNA

“…The physiological importance of Z-conformation nucleic acids is still an ongoing debate, even after more than four decades of study [ 18 ]. While both Z-DNA and Z-RNA have been implicated in separate biological processes, concrete proof of their existence in vivo remains elusive and/or difficult to detect [ 13 , 14 , 15 , 18 , 155 ].…”

“…The physiological importance of Z-conformation nucleic acids is still an ongoing debate, even after more than four decades of study [ 18 ]. While both Z-DNA and Z-RNA have been implicated in separate biological processes, concrete proof of their existence in vivo remains elusive and/or difficult to detect [ 13 , 14 , 15 , 18 , 155 ]. As DNA and RNA exist in drastically different contexts within the cell, it becomes imperative to understand the conditions that may stabilize the Z-conformation for each in their respective environments.…”

“…In contrast to what is known from studied sequence contexts, many chemical factors affecting the B-to-Z and A-to-Z transition differ between DNA and RNA. In the following section we will discuss select examples of chemical factors, excluding topological conditions and protein binding (for more information, see reviews [ 14 , 16 , 18 ] and references therein), and how they affect the equilibrium of the transition to the Z-conformation.…”

“…In this review, we aim to discuss some of the inherent structural properties of Z-RNA and Z-DNA, and how they affect the Z-DNA/RNA formation, sequence preferences, stability, as well as energetics. While other reviews have focused more specifically on Z-DNA structure [ 13 , 14 ], the crystallization of Z-DNA sequences [ 15 ], Z-conformation biology [ 11 , 12 , 16 , 17 , 18 ], and the mechanisms of the B-to-Z transition [ 19 , 20 ], we focus in particular on extending our knowledge about Z-RNA formation and its relevance to biology.…”

Z-Form Adoption of Nucleic Acid is a Multi-Step Process Which Proceeds through a Melted Intermediate

“…Adenosine deaminase acting on RNA 1 (ADAR1) is an Ato-I editase which regulates the innate immune response by preventing activation of dsRNA sensors. 35,56 The longer isoform of ADAR1 contains an N-terminal Zα domain, which has been shown to play an important role in ADAR1's function. 39,95,96 Our finding that inosylation of the r(CpG) 6 construct increased its Z-form adoption rate to a comparable level as that of the r(CpG) 3 was striking.…”