ADAR Enzymes

ADAR is a family of naturally occurring enzymes which contains ADAR1, ADAR2, and ADAR3. The job of ADAR enzymes is to moderate the editing of adenosine to inosine in RNA. ADAR1 is expressed everywhere, however, ADAR2 and ADAR3 are most commonly expressed in the brain. The parts that compose these enzymes are a double stranded RNA, a binding domain of roughly 65 amino acids, and a deaminase domain. 

The job of ADAR is to convert adenosine into inosine in double-stranded RNAs. This process, known as A-to-I editing, is crucial as it changes RNA molecules. When ADAR1 is deficient, it can create inflammatory diseases that are characterised by sudden cytokine production. Specifically, in humans, when ADAR has a sudden mutation that leads to a dissipation of function coupled with a dominant negative mutation causes Aicard-Goutieres syndrome: a syndrome that affects the roles of the brain, the immune system and the skin. There also has been connections found between ADAR1 level depletion and genetic disorders like bilateral striatal necrosis and dyschromatosis symmetrica hereditaria. 

The A-to-I editing is speculated to be a crucial way of creating diversity among proteins by changing the codon in mRNAs. They moderate the levels of cellular dsRNAs. ADARs edit adenosines to inosines, which mainly lead to recoding of transcripts and peptides. However, this can also lead to deamination of up to 50% of the adenosines if the ADAR are changing long duplexes. However, the consequences of this editing are still difficult to understand. 

The three family members of ADAR: ADAR1, ADAR2, and ADAR3, have four known isoforms: ADAR1p150, ADAR1p110, ADAR2 and ADAR3. Out of the three family members, ADAR3 is the only one known that is thought to be catalytically inactive. ADAR1p110 localizes to the nucleus, in contrast ADAR1p150 goes out and in the nucleus, and is found to collect in the cytoplasm. ADAR1p110 and ADAR2 are primarily located in the nucleolus, but their location depends on the functional dsRBDs. 

There are multiple genetic model systems that showcase the connection between ADAR deficiencies and a properly working nervous system. There have also been many studies that have provided evidence showing the connection between  RNA editing and multiple nervous system disorders. Some such examples are suicidal depression, schizophrenia, epilepsy, and amyotrophic lateral sclerosis. Other studies have provided that specifically that mutations in the ADAR1 gene is linked to DSH, which is an autosomal skin pigmentation disorder. 

Currently, deficiencies in the ADAR enzymes have been linked to diseases and disorders. However, A-to-I editing can also bring consequences into play, a topic that researchers are still exploring and understanding. 

References:

Han , Ruofan, and Robert MacLaren. “Adar - an Overview | Sciencedirect Topics.” ScienceDirect, www.sciencedirect.com/topics/medicine-and-dentistry/adar. Accessed 24 Nov. 2025. 

Savva, Yiannis A, et al. “The ADAR Protein Family - Genome Biology.” BioMed Central, BioMed Central, 28 Dec. 2012, genomebiology.biomedcentral.com/articles/10.1186/gb-2012-13-12-252. 

Tomaselli, Sara, et al. “Adar Enzyme and MIRNA Story: A Nucleotide That Can Make the Difference.” International Journal of Molecular Sciences, U.S. National Library of Medicine, 19 Nov. 2013, pmc.ncbi.nlm.nih.gov/articles/PMC3856091/#:~:text=5.6.&text=In%20addition%20to%20A%2Dto,still%20to%20be%20fully%20discovered. 

Rehwinkel, Jan, and Parinaz Mehdipour. “ADAR1: From Basic Mechanisms to Inhibitors.” Cellpress, 2025, www.cell.com/trends/cell-biology/fulltext/S0962-8924(24)00120-X. 

“Aicardi-Goutières Syndrome: Medlineplus Genetics.” MedlinePlus, U.S. National Library of Medicine, medlineplus.gov/genetics/condition/aicardi-goutieres-syndrome/#:~:text=Growth%20of%20the%20brain%20and%20skull%20slows,with%20Aicardi%2DGouti%C3%A8res%20syndrome%20have%20profound%20intellectual%20disabilities. Accessed 23 Nov. 2025. 

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