Adenosine Deaminase Acting on RNA 2 (ADAR2) is an enzyme that modifies genetic instructions after they have been transcribed from DNA into RNA. Acting as an “RNA editor,” ADAR2 performs a specific type of post-transcriptional change necessary for proper cellular function. Its primary role involves a chemical substitution on the RNA molecule, fundamentally altering the code used to build proteins. Because this modification changes the functional output of a gene without touching the underlying DNA sequence, ADAR2 is recognized as a significant regulator of genetic information in human biology.
The Molecular Mechanism of A-to-I Editing
The process catalyzed by ADAR2 is known as Adenosine-to-Inosine (A-to-I) RNA editing, a modification that occurs on double-stranded RNA (dsRNA) molecules. ADAR2 targets the adenine base (A) within the RNA and converts it into inosine (I) through a hydrolytic deamination reaction at the C6 position of the base.
The functional impact of this chemical change is significant because the cell’s machinery interprets inosine as if it were guanosine (G). This means that a codon, the three-base sequence that specifies an amino acid, can change from an A-containing codon to a G-containing codon. The resulting protein will therefore contain an amino acid that was not originally encoded by the gene’s DNA sequence.
The enzyme achieves site-selective editing by recognizing the double-stranded structure of the RNA, often formed by the transcript folding back on itself. While ADAR enzymes generally bind to dsRNA without strict sequence specificity, ADAR2 exhibits a preference for certain sites. This selectivity is influenced by the immediate structural environment around the editing site, including the presence of mismatches or loops in the RNA duplex. The conversion of an adenosine to an inosine can thus change the resulting protein’s function, influence RNA stability, and alter how the transcript is spliced.
ADAR2’s Functions in Healthy Physiology
ADAR2 activity is concentrated in the central nervous system, where it maintains proper neuronal communication. The most recognized physiological function is the editing of messenger RNA (mRNA) that codes for the GluA2 subunit of the AMPA receptor, a major neurotransmitter receptor in the brain. This specific event, known as the Q/R editing site, converts a codon for glutamine (Q) in the pre-mRNA to one for arginine (R) in the mature mRNA.
The replacement of the neutral amino acid glutamine with the positively charged arginine within the ion-conducting pore of the GluA2 subunit is essential for function. This single amino acid change causes the resulting AMPA receptor to become impermeable to calcium ions, which is the standard state for most AMPA receptors in the adult brain. The high efficiency of this editing, typically near 100% in healthy neurons, regulates synaptic transmission and prevents excessive calcium influx.
ADAR2 also contributes to maintaining the integrity of the cell’s RNA landscape. The enzyme edits various non-coding RNAs, including microRNA (miRNA) precursors, which are short molecules that regulate gene expression. By editing these precursors, ADAR2 can alter the expression or function of the mature miRNA, influencing downstream cellular processes. ADAR2 also participates in an autoregulatory loop, editing its own pre-mRNA to suppress its expression, which helps maintain a balanced level of editing activity.
Link to Neurological Disorders
When ADAR2 editing fails, it leads to severe consequences, particularly in the nervous system. The most direct and well-documented link is to Amyotrophic Lateral Sclerosis (ALS), a progressive neurodegenerative disease characterized by the death of motor neurons. In the motor neurons of most sporadic ALS patients, ADAR2 expression is significantly reduced, causing a failure to fully edit the GluA2 mRNA transcript.
This inefficient editing causes a portion of the AMPA receptors in motor neurons to retain the unedited glutamine (Q) at the Q/R site, making them permeable to calcium ions. The resulting excessive calcium influx into the motor neurons is toxic, triggering a cascade of cellular damage and ultimately leading to the death of these cells. Progressive downregulation of ADAR2 activity is hypothesized to be a critical factor in the initiation and progression of sporadic ALS.
Mouse models have demonstrated that even a half-normal level of ADAR2 activity is not sufficient to edit all GluA2 mRNA in motor neurons, leading to degeneration and an ALS-like phenotype. The failure of GluA2 editing is a disease-specific and motor neuron-selective event in ALS, demonstrating the impact of this single enzymatic failure. Furthermore, ADAR2 dysfunction is also implicated in conditions such as some forms of epilepsy, where compromised editing of other ion channel subunits, like the Kainate receptor subunit GluK2, contributes to neuronal hyperexcitability.
Roles in Cancer and Immune Response
The influence of ADAR2 extends beyond the nervous system, affecting both cancer and the immune system. In the context of cancer, ADAR2 can act as either a tumor suppressor or an oncogenic driver, depending on the specific cancer type and the transcripts it edits. In several brain cancers, such as high-grade astrocytoma and glioblastoma multiforme, ADAR2 activity or expression is frequently decreased.
This downregulation promotes tumor progression by failing to edit specific transcripts, including those involved in cell cycle regulation or apoptosis. Conversely, the enzyme’s overexpression is sometimes observed in other tumors. This suggests that ADAR2’s role is determined by the specific set of RNA targets that are dysregulated within the tumor environment.
In the immune system, ADAR2 contributes to differentiating between the body’s own RNA (self) and foreign RNA, such as that from viruses. A-to-I editing of double-stranded RNA helps to suppress the innate immune response that would otherwise be triggered by unedited, endogenous dsRNA. This editing is important for preventing the inappropriate activation of interferon signaling pathways, which can lead to chronic inflammation and autoimmune conditions. ADAR2’s ability to edit microRNAs also gives it a regulatory role in immune cell function, modulating the inflammatory response and contributing to cellular homeostasis.