Dynamic regulation of Z-DNA in the mouse prefrontal cortex by the RNA-editing enzyme Adar1 is required for fear extinction
Author
Marshall, PR; Zhao, Q; Li, X; Wei, W; Periyakaruppiah, A; Zajaczkowski, EL; Leighton, LJ; Madugalle, SU; Basic, D; Wang, Z; ...Date
2020-05-04Source Title
Nature NeurosciencePublisher
NATURE PUBLISHING GROUPUniversity of Melbourne Author/s
Walkley, CarlAffiliation
Medicine and RadiologyMetadata
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Journal ArticleCitations
Marshall, 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-+. https://doi.org/10.1038/s41593-020-0627-5.Access Status
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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269834Abstract
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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