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 () and Pierre Barraud ()
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Allegra Mboukou: Institut de biologie physico-chimique
Vinod Rajendra: Medical University of Vienna
Serafina Messmer: Medical University of Vienna
Therese C. Mandl: Medical University of Vienna
Marjorie Catala: Institut de biologie physico-chimique
Carine Tisné: Institut de biologie physico-chimique
Michael F. Jantsch: Medical University of Vienna
Pierre Barraud: Institut de biologie physico-chimique

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract Adenosine-to-inosine editing is catalyzed by adenosine deaminases acting on RNA (ADARs) in double-stranded RNA (dsRNA) regions. Although three ADARs exist in mammals, ADAR1 is responsible for the vast majority of the editing events and acts on thousands of sites in the human transcriptome. ADAR1 has been proposed to form a stable homodimer and dimerization is suggested to be important for editing activity. In the absence of a structural basis for the dimerization of ADAR1, and without a way to prevent dimer formation, the effect of dimerization on enzyme activity or site specificity has remained elusive. Here, we report on the structural analysis of the third double-stranded RNA-binding domain of ADAR1 (dsRBD3), which reveals stable dimer formation through a large inter-domain interface. Exploiting these structural insights, we engineered an interface-mutant disrupting ADAR1-dsRBD3 dimerization. Notably, dimerization disruption did not abrogate ADAR1 editing activity but intricately affected editing efficiency at selected sites. This suggests a complex role for dimerization in the selection of editing sites by ADARs, and makes dimerization a potential target for modulating ADAR1 editing activity.

Date: 2024
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DOI: 10.1038/s41467-024-53777-2

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