RT Journal Article
SR Electronic
T1 Dynamic DNA structure states interact with the RNA editing enzyme ADAR1 to modulate fear extinction memory
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 641209
DO 10.1101/641209
A1 Paul R. Marshall
A1 Qiongyi Zhao
A1 Xiang Li
A1 Wei Wei
A1 Abi Malathi
A1 Esmi Zajaczkowski
A1 Laura Leighton
A1 Sachithrani Madugalle
A1 Dean Basic
A1 Ziqi Wang
A1 Jiayu Yin
A1 Wei-Siang Liau
A1 Carl Walkley
A1 Timothy W. Bredy
YR 2019
UL http://biorxiv.org/content/early/2019/05/20/641209.abstract
AB RNA modification has recently emerged as an important mechanism underlying gene diversity linked to behavioral regulation. The conversion of adenosine to inosine by the ADAR family of enzymes is a particularly important RNA modification as it impacts the physiological readout of protein-coding genes. However, not all variants of ADAR appear to act solely on RNA. ADAR1 binds directly to DNA when it is in a non-canonical, left handed, “Z” conformation, but little is known about the functional relevance of this interaction. Here we report that ADAR1 binds to Z-DNA in an activity-dependent manner and that fear extinction learning leads to increased ADAR1 occupancy at DNA repetitive elements, with targets adopting a Z-DNA structure at sites of ADAR1 recruitment. Knockdown of ADAR1 leads to an inability to modify a previously acquired memory trace and this is associated with a concomitant change in DNA structure and a decrease in RNA editing. These findings suggest a novel mechanism of learning-induced gene regulation whereby ADAR1 physically interacts with Z-DNA in order to mediate its effect on RNA, and both are required for memory flexibility following fear extinction learning.