While DNA is often considered a fixed blueprint, biological information can be modified after being copied into ribonucleic acid (RNA). This process, known as RNA editing, involves enzymes that alter the RNA message before it guides protein creation, adding a layer of control over how genetic instructions are expressed.
Among the most widespread forms of this is ADAR RNA editing, a mechanism of post-transcriptional modification where the RNA message itself is altered. This system allows organisms to fine-tune their cellular functions, creating molecular diversity that goes beyond the static information held within the genome.
The Mechanism of ADAR Editing
ADAR stands for Adenosine Deaminase Acting on RNA. In mammals, the primary enzymes are ADAR1 and ADAR2, which exclusively target RNA that has folded into a double-stranded structure (dsRNA). This structure acts as a platform for the ADAR enzymes to bind and perform their function. Most target sites are in non-coding RNA regions. ADAR1 is broadly expressed and handles widespread editing, while ADAR2 is more prominent in the central nervous system and performs highly specific edits.
The core chemical reaction is a deamination, where an adenosine (A) nucleotide on an RNA strand is converted into inosine (I) by removing an amine group. The cell’s protein-building machinery, the ribosome, then interprets inosine as if it were guanosine (G). This molecular mimicry effectively transforms an A in the RNA code into a G, which can change the instructions for building a protein or affect other regulatory processes.
Biological Functions of RNA Editing
One direct outcome of A-to-I editing is protein recoding, where an edit alters the amino acid produced from an RNA sequence. This creates a new version of a protein with a different function from the same gene. For example, editing of the GRIA2 transcript for glutamate receptors in the brain at the Q/R site is performed by ADAR2. This single, nearly 100% efficient change is necessary to produce a functional receptor, and its absence is lethal in mice.
ADAR editing also regulates the innate immune system. Cells contain their own double-stranded RNA (dsRNA) that can resemble viral RNA. ADAR1 edits these self-dsRNAs, marking them as “self” to prevent the immune system from mistakenly identifying them as foreign. Without this editing, cellular sensors like MDA5 would trigger a powerful antiviral response, leading to harmful inflammation.
ADAR editing contributes to other layers of gene regulation. It can influence RNA splicing, the process of joining RNA segments to form a final message. By altering sequences near splice sites, editing can generate different protein isoforms from a single gene. ADAR can also modify microRNAs (miRNAs), small molecules that regulate gene expression. Editing a miRNA can alter its target genes, while editing miRNA binding sites on messenger RNA can affect its stability.
The Role of ADAR in Human Health and Disease
Malfunctions in ADAR editing are linked to human diseases, particularly autoimmune disorders. When ADAR1 activity is reduced by mutations, the cell’s own dsRNA is left unedited. The immune system then misidentifies this self-RNA as viral, triggering a chronic inflammatory response. This mechanism is the basis for Aicardi-Goutières syndrome (AGS), a severe childhood autoimmune disease that can cause progressive brain damage.
Dysregulation of RNA editing is also implicated in neurological disorders. Since ADAR2 is highly expressed in the brain and responsible for editing transcripts like glutamate receptors, its malfunction can have serious consequences. Reduced ADAR2 activity is linked to conditions such as epilepsy and amyotrophic lateral sclerosis (ALS). The precise editing of neural transcripts is necessary for maintaining proper synaptic function and neuronal health.
The role of ADAR in cancer is complex, as its activity can be either tumor-suppressing or tumor-promoting. In some cancers like glioblastoma, reduced ADAR2 activity is observed. Conversely, ADAR1 is often overexpressed in many cancers, including breast and liver cancer, where it is associated with increased malignancy. This hyperactivity can promote cell proliferation and help cancer cells evade the immune system.
Therapeutic and Research Applications
The precision of ADAR enzymes has opened new avenues for therapeutic development. A strategy called site-directed RNA editing aims to use the body’s own ADAR enzymes to correct disease-causing mutations at the RNA level. This approach uses engineered guide RNAs (gRNAs) that bind to a target RNA and recruit ADAR enzymes to make a desired A-to-I edit. This could potentially reverse G-to-A mutations, which are common in human genetic diseases.
This RNA-level intervention is a flexible alternative to permanent DNA editing like CRISPR. Because RNA is a transient molecule, any edits are not permanent and their effects are reversible, minimizing the risk of lasting off-target effects. This makes the approach suitable for conditions requiring temporary therapeutic action. Research is underway to apply this technology to a variety of genetic disorders.
Beyond therapeutics, the ADAR system is a valuable research tool. By designing guide RNAs to target specific genes, scientists can use site-directed editing to study gene function with high precision. Observing the effects of a targeted RNA edit helps researchers understand the role of a specific amino acid in a protein or the function of a genetic sequence, accelerating the investigation of biological pathways.