ADAR1, an enzyme involved in RNA editing
In our cells, RNA editing is a fundamental process that occurs after transcription, that is, after the formation of RNA from the DNA sequence, and which allows making subtle changes to genetic information before it is translated into proteins. One of the most common forms of editing is that which transforms adenosine (A) into inosine (I), a reaction catalyzed by specific enzymes, called ADARs. Among these enzymes, ADAR1 is the most active and operates at thousands of sites across the human transcriptome. However, how ADAR1 precisely recognizes and selects these editing sites remains poorly understood, particularly the role of dimerization (two copies of the enzyme binding together) in this activity was unknown.
What role does dimerization play in ADAR1 activity and editing site selection?
To better understand the specificity of recognition of editing sites, scientists undertook a detailed study on the structure of ADAR1, recently published in Nature Communications. Using an approach combining the structural analysis of the enzyme and the creation of mutants, they showed that a region corresponding to a double-stranded RNA binding domain of ADAR1 allows dimerization through a large interface between two ADAR1 molecules. By modifying this interface, the researchers were able to disrupt the formation of dimers without completely blocking editing activity, which affected the efficiency of editing at specific sites.
By disrupting dimerization, the researchers observed a selective change in the efficiency of RNA editing at specific sites, suggesting a complex and finely modulated role of dimerization in the recognition of editing sites by ADAR1. This result is important for fundamental research, because it reveals a new dimension of regulation of the enzymatic activity of ADAR1.
Modulate ADAR1 activity in pathologies where deregulation of RNA editing is observed?
Furthermore, this discovery opens up interesting therapeutic perspectives. By specifically targeting ADAR1 dimerization, it could be possible to modulate its activity with possible benefits in certain pathologies where deregulation of RNA editing is involved, such as in certain autoimmune diseases. Furthermore, manipulating ADAR1 activity could ultimately become a complementary approach in the treatment of certain cancers by immunotherapy.
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