Journal article

Dynamic regulation of Z-DNA in the mouse prefrontal cortex by the RNA-editing enzyme Adar1 is required for fear extinction

Paul R Marshall, Qiongyi Zhao, Xiang Li, Wei Wei, Ambika Periyakaruppiah, Esmi L Zajaczkowski, Laura J Leighton, Sachithrani U Madugalle, Dean Basic, Ziqi Wang, Jiayu Yin, Wei-Siang Liau, Ankita Gupte, Carl R Walkley, Timothy W Bredy

Nature Neuroscience | NATURE PUBLISHING GROUP | Published : 2020

Abstract

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 memo..

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Grants

Awarded by National Institutes of Health


Awarded by National Health and Medical Research Council


Awarded by ARC


Funding Acknowledgements

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.