In a study recently published in "Nature Communications", researchers from MedUni Vienna and the Centre National de Recherche Scientifique (CNRS) in Paris show how dimerization of the RNA editing enzyme ADAR selectively alters its specificity at certain sequences. The knowledge gained opens up new possibilities to modulate the functions of ADAR1 via its dimerization for therapeutic purposes in autoimmune diseases or cancer.
RNA editing is an essential process in mammals, including humans. By selectively deaminating one of the four letters of the genetic alphabet, adenosines (A) are changed into inosines (I) at the RNA level. This common form of RNA editing can change genetic information, but is also used to distinguish the body’s own RNAs from foreign RNAs such as viral RNAs. The enzyme ADAR1 acts on thousands of adenosines in human cells, leaving behind specific modification patterns that are important for distinguishing between foreign and self RNAs. Exactly how ADAR1 recognizes and selects these sites is not yet fully known.
In order to better understand the function and specificity of ADAR1, the researchers analysed the atomic structure of the enzyme and discovered that the enzyme dimerizes. "Through targeted mutations in the enzyme that prevent dimer formation, we were able to show that the pattern of RNA editing depends on the dimer formation of the enzyme," explains Michael Jantsch (Division of Cell and Developmental Biology, Center for Anatomy and Cell Biology, MedUni Vienna), who led the study together with Pierre Barraud (Institut de Bologie Physico-Chimique, CNRS).
The study results therefore demonstrate selective regulation of enzyme activity through dimer formation. Since the changes inserted into RNA sequences by ADAR1 are also recognized by the immune system, altered modification patterns can also lead to an activation of the immune system. By specifically influencing ADAR1 dimerization, it may therefore be possible to regulate the immunogenicity of certain cells, such as cancer cells, which could lead to new therapeutic approaches.
Publication: Nature Communications
Dimerization of ADAR1 modulates site-specificity of RNA editing.
Allegra Mboukou, Vinod Rajendra, Serafina Messmer, Therese C. Mandl, Marjorie Catala, Carine Tisné, Michael F. Jantsch & Pierre Barraud.
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