Dynamic regulation of Z-DNA in the mouse prefrontal cortex by the RNA-editing enzyme Adar1 is required for fear extinction
AuthorMarshall, PR; Zhao, Q; Li, X; Wei, W; Periyakaruppiah, A; Zajaczkowski, EL; Leighton, LJ; Madugalle, SU; Basic, D; Wang, Z; ...
Source TitleNature Neuroscience
PublisherNATURE PUBLISHING GROUP
University of Melbourne Author/sWalkley, Carl
AffiliationMedicine (St Vincent's)
Document TypeJournal Article
CitationsMarshall, P. R., Zhao, Q., Li, X., Wei, W., Periyakaruppiah, A., Zajaczkowski, E. L., Leighton, L. J., Madugalle, S. U., Basic, D., Wang, Z., Yin, J., Liau, W. -S., Gupte, A., Walkley, C. R. & Bredy, T. W. (2020). Dynamic regulation of Z-DNA in the mouse prefrontal cortex by the RNA-editing enzyme Adar1 is required for fear extinction. NATURE NEUROSCIENCE, 23 (6), pp.718-729. https://doi.org/10.1038/s41593-020-0627-5.
Access StatusAccess this item via the Open Access location
Open Access URLAccepted version
DNA forms conformational states beyond the right-handed double helix; however, the functional relevance of these noncanonical structures in the brain remains unknown. Here we show that, in the prefrontal cortex of mice, the formation of one such structure, Z-DNA, is involved in the regulation of extinction memory. Z-DNA is formed during fear learning and reduced during extinction learning, which is mediated, in part, by a direct interaction between Z-DNA and the RNA-editing enzyme Adar1. Adar1 binds to Z-DNA during fear extinction learning, which leads to a reduction in Z-DNA at sites where Adar1 is recruited. Knockdown of Adar1 leads to an inability to modify a previously acquired fear memory and blocks activity-dependent changes in DNA structure and RNA state-effects that are fully rescued by the introduction of full-length Adar1. These findings suggest a new mechanism of learning-induced gene regulation that is dependent on proteins that recognize alternate DNA structure states, which are required for memory flexibility.
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