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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The authors gratefully acknowledge grant support from the National Institutes of Health (R01MH105398-TWB) and the National Health and Medical Research Council (GNT1145172 and GNT1160823-TWB), the ARC (GNT190101078-XL), the Westpac Future Scholars program (E.L.Z., L.J.L. and S.U.M.) and postgraduate scholarships from the Natural Sciences and Engineering Research Council (P.R.M.) and the University of Queensland (P.R.M., E.L.Z., L.J.L., D.B., J.Y. and S.U.M.). We would also like to thank R. Tweedale for helpful editing of the manuscript.
The authors declare no competing interests.
Peer review information Nature Neuroscience thanks Alan Herbert, Larry Zweifel and the other, anonymous reviewer(s) for their contribution to the peer review of this work.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Data from this paper can be accessed at PRJNA545193.
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Marshall, P.R., Zhao, Q., Li, X. et al. Dynamic regulation of Z-DNA in the mouse prefrontal cortex by the RNA-editing enzyme Adar1 is required for fear extinction. Nat Neurosci 23, 718–729 (2020). https://doi.org/10.1038/s41593-020-0627-5
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