ADAR

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ADAR: what it is and why it matters

ADAR stands for adenosine deaminase acting on RNA. It’s a family of enzymes that edit RNA by converting one building block, adenosine, into another, inosine. This change happens in double-stranded RNA (dsRNA) and can alter how the RNA is read, which can affect the protein made from the RNA, how the RNA is spliced, and how small RNA molecules are controlled.

The ADAR family in humans
- ADAR1 (also called ADAR) and ADAR2 (ADARB1) are active editors found in many tissues.
- ADAR3 (ADARB2) is mainly in the brain and is not catalytically active.
- ADAR1 comes in two forms: p150 (mostly in the cytoplasm and can move to the nucleus) and p110 (primarily in the nucleus).
- All ADARs have one catalytic deaminase domain and several dsRNA-binding domains. ADAR1 has extra Z-DNA binding domains (Zα and Zβ).

How ADAR editing works
- It changes adenosine (A) to inosine (I) in dsRNA. The cell reads inosine as if it were guanosine (G).
- This can change codons in mRNA, potentially altering the protein’s amino acid sequence.
- It can also affect RNA splicing, stability, and interactions with other RNAs and proteins.
- Most editing occurs in noncoding regions (like untranslated regions and repetitive elements) but can also influence microRNAs and circRNAs.

Important details about ADARs
- Dimerization: ADAR1 and ADAR2 can form dimers; ADAR3 does not. Dimerization isn’t strictly required for activity, but for ADAR1, pairing through dsRBD3 can happen without RNA.
- Localization and activity differ by isoform and enzyme type, influencing where editing happens in the cell.

ADARs in health and disease
- Immune system and interferon: ADAR1 helps regulate the immune response to RNA. When ADAR1 doesn’t work properly, cells can overreact to dsRNA, leading to inflammation.
- Aicardi–Goutières syndrome (AGS): mutations in ADAR1, especially in the Zα domain, can cause AGS, a genetic inflammatory disorder affecting the brain and skin.
- Nervous system and movement disorders: loss of ADAR2 activity in motor neurons is linked to ALS-like symptoms in animals, showing editing is important for neuron health.
- Cancer: the balance between ADAR1 and ADAR2 editing can influence cancer. In some cancers, ADAR1 is higher and may promote tumor growth, while ADAR2 can act as a tumor suppressor in others. ADARs also affect microRNAs, which can impact cancer progression.
- Viral infections: many viruses are edited by ADAR1, which can either help the virus by promoting mutations or help the host by inhibiting viral replication, depending on the context. ADAR1 activity has been seen in infections like HIV, measles, and influenza.

Evolution and distribution
- ADAR enzymes emerged early in animal evolution and are highly conserved across metazoans.
- They are common in many animals but are not found in all non-metazoan organisms.

History
- ADAR was discovered in 1987 by researchers studying how cells regulate RNA in embryos. In 1988, further work showed that the editing was caused by a dsRNA-specific enzyme.

In short
ADAR enzymes edit RNA after it is made, changing A to I and thus influencing which proteins are produced, how RNAs are processed, and how cells respond to viruses. They play important roles in brain function, immune regulation, and cancer, and malfunctions can lead to serious diseases.