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Dynamic regulation of Z-DNA in the mouse prefrontal cortex by the RNA-editing enzyme Adar1 is required for fear extinction
Marshall, Paul R. Zhao, Qiongyi Li, Xiang Wei, Wei Periyakaruppiah, Ambika Zajaczkowski, Esmi L. J. Leighton, Laura Madugalle, Sachithrani U. Basic, Dean Wang, Ziqi
Marshall, Paul R.
Zhao, Qiongyi
Li, Xiang
Wei, Wei
Periyakaruppiah, Ambika
Zajaczkowski, Esmi L.
J. Leighton, Laura
Madugalle, Sachithrani U.
Basic, Dean
Wang, Ziqi
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 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.
Keywords
Date
2020
Type
Journal article
Journal
Nature Neuroscience
Book
Volume
23
Issue
6
Page Range
718-729
Article Number
ACU Department
Mary MacKillop Institute for Health Research
Faculty of Health Sciences
Faculty of Health Sciences
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Files
Relation URI
Source URL
Event URL
Open Access Status
Published as green open access
License
File Access
Open
Controlled
Controlled