Poster abstracts

Poster number 77 submitted by Reshma Raghava Kurup

Molecular function of ADAR3 in neuronal activity

Reshma Raghava Kurup (Genome, Cell and Developmental Biology Program, Indiana University), Heather A. Hundley (Medical Sciences Program, Indiana University School of Medicine, Bloomington, IN 47405)

Abstract:
ADARs (Adenosine deaminase that act on RNA) carry out adenosine (A) to inosine (I) editing, one of the most abundant RNA modifications [1]. In humans, there are three ADAR family members, ADAR1, ADAR2 and ADAR3. While ADAR1 and ADAR2 are ubiquitous, ADAR3 is specifically expressed in the nervous system. ADAR1 and ADAR2 are the major editing enzymes whereas ADAR3 lacks editing activity [2]. ADAR editing activity is required for normal neurological function, and loss of ADAR activity is associated with several pathologies including neurodegenerative diseases, cancer, auto-immune diseases and metabolic disorders. Recently our lab has demonstrated the role of ADAR3 as a negative regulator of RNA editing [3]. ADAR3 has the conserved domains of catalytically active deaminases and can directly bind to RNA, but ADAR3 inhibits editing of transcripts.
A recent study determined that ADAR3 deficient mice exhibit increased anxiety and deficits in memory formation [4]. In addition, KCl mediated depolarization of the neuroblastoma cell line, SH-SY5Y, reduced expression of a long non-coding RNA that regulates transcription of ADAR3 and resulted in differential expression of genes involved in proper neuronal function [5, 6]. Some of these genes were also differentially expressed in ADAR3 deficient mice that exhibited cognitive deficits. Therefore, we are investigating the role of ADAR3 in response to neuronal stimulation. We found that there is increased expression of ADAR3 upon KCl treatment. In addition, we observed changes in subcellular localization of ADAR3. The upregulated ADAR3 expression and translocation of ADAR3 in response to neuronal activity suggests ADAR3 plays an important role in regulation of signaling pathways linked to neuronal activation.

References:
1. Walkley, C. R. & Li, J. B. Rewriting the transcriptome : adenosine-to-inosine RNA editing by ADARs. Genome Biol. 18 (2017).
2. Chen, C. et al. A third member of the RNA-specific adenosine deaminase gene family ADAR3 contains both single and double stranded RNA binding domains. RNA 6 (2000).
3. Oakes, E. et al. Adenosine Deaminase That Acts on RNA 3 (ADAR3) Binding to Glutamate Receptor Subunit B PremRNA Inhibits RNA Editing in Glioblastoma. J Biol Chem 3 (2017).
4. Mladenova, D. et al. Adar3 Is Involved in Learning and Memory in Mice. 12 (2018).
5. Hirose, T. et al. NEAT1 long noncoding RNA regulates transcription via protein sequestration within subnuclear bodies. 25 (2014).
6. Barry, G. et al. The long non-coding RNA NEAT1 is responsive to neuronal activity and is associated with hyperexcitability states. Sci. Rep. 7 (2017).

Keywords: ADAR3