**ADAR (Adenosine Deaminase Acting on RNA)** is a family of enzymes that catalyze the conversion of [[adenosine]] (A) to [[inosine]] (I) in double-stranded RNA (dsRNA) through a process known as **RNA editing**. This post-transcriptional modification alters [[RNA]] [[sequence]]s, affecting gene expression, splicing, RNA stability, and translation.

### **Types of ADAR Enzymes**
1. **[[ADAR1]]**:
   - Ubiquitously expressed with two isoforms:
     - **p150**: Induced by interferons and predominantly cytoplasmic.
     - **p110**: Constitutively expressed and localized in the nucleus.
   - Plays a crucial role in innate immunity by modifying endogenous dsRNA to prevent inappropriate activation of immune sensors like MDA5.

2. **ADAR2**:
   - Primarily expressed in the brain and essential for editing transcripts related to neurotransmission and neuronal function.
   - Key substrate: **GRIA2** mRNA, encoding a subunit of the AMPA receptor, where editing impacts calcium permeability.

3. **ADAR3**:
   - Found mainly in the brain but has no known enzymatic activity. Its role may involve modulating ADAR1 and ADAR2 activity.

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### **Functions of ADAR**
1. **RNA Editing**:
   - Inosine is read as guanosine by the translational machinery, leading to changes in the encoded protein.
   - Critical substrates include:
     - **GRIA2 (glutamate receptor)**: Affects calcium ion flow in neurons.
     - **GABRA3 (GABA receptor)**: Impacts inhibitory neurotransmission.

2. **Innate Immunity Regulation**:
   - ADAR1 prevents immune sensors like **MDA5** and **PKR** from recognizing self-dsRNA, thus avoiding autoimmunity.

3. **Transcriptome Diversification**:
   - Editing expands the functional repertoire of proteins and fine-tunes gene expression.

4. **Role in Development and Survival**:
   - ADAR1 is essential for embryonic development and immune homeostasis.

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### **ADAR in Diseases**
1. **Cancer**:
   - Dysregulation of ADAR1 is associated with tumor progression and immune evasion:
     - Overexpression of ADAR1 can promote editing of transcripts that favor cell survival and metastasis.
     - ADAR1 contributes to resistance to immune checkpoint inhibitors by editing dsRNA and evading immune activation.

2. **Neurological Disorders**:
   - Mutations or dysregulation in ADAR2-mediated editing (e.g., GRIA2 transcript) are linked to diseases like epilepsy, ALS, and schizophrenia.

3. **Autoimmune Diseases**:
   - Loss of ADAR1 activity can lead to aberrant recognition of self-dsRNA by innate immune sensors, causing autoinflammatory conditions such as Aicardi-Goutières syndrome.

4. **Viral Infections**:
   - ADAR1 can edit viral RNA, influencing viral replication and immune recognition.

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### **Therapeutic Potential of ADAR**
1. **Gene Editing Tools**:
   - Harnessing ADAR's ability to edit RNA for precise therapeutic modifications (e.g., correcting mutations at the RNA level).
   - Engineered ADAR systems, such as **REPAIR (RNA Editing for Programmable A-to-I Replacement)**, are under investigation.

2. **Targeting ADAR1 in Cancer**:
   - Inhibiting ADAR1 to enhance immune recognition of tumor cells is a promising immunotherapeutic strategy.

3. **Restoring Normal Editing in Neurological Disorders**:
   - Therapeutic approaches aim to correct or restore ADAR2-mediated editing in diseases like ALS.

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### **Research Directions**
1. Understanding the balance between beneficial and detrimental RNA editing by ADARs in cancer and immunity.
2. Development of small-molecule modulators or gene therapies targeting ADARs.
3. Exploring ADAR as a diagnostic and prognostic biomarker in various diseases.