Dimerization of ADAR1 modulates site-specificity of RNA editing
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....
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-11-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-53777-2 |
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| author | Allegra Mboukou Vinod Rajendra Serafina Messmer Therese C. Mandl Marjorie Catala Carine Tisné Michael F. Jantsch Pierre Barraud |
| author_facet | Allegra Mboukou Vinod Rajendra Serafina Messmer Therese C. Mandl Marjorie Catala Carine Tisné Michael F. Jantsch Pierre Barraud |
| author_sort | Allegra Mboukou |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-bec12aa3a4b14de3ba77fce667ddf20a |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-bec12aa3a4b14de3ba77fce667ddf20a2024-11-24T12:33:18ZengNature PortfolioNature Communications2041-17232024-11-0115111410.1038/s41467-024-53777-2Dimerization of ADAR1 modulates site-specificity of RNA editingAllegra Mboukou0Vinod Rajendra1Serafina Messmer2Therese C. Mandl3Marjorie Catala4Carine Tisné5Michael F. Jantsch6Pierre Barraud7Expression génétique microbienne, Université Paris Cité, CNRS, Institut de biologie physico-chimiqueDivision of Cell and Developmental Biology, Center for Anatomy and Cell Biology, Medical University of ViennaDivision of Cell and Developmental Biology, Center for Anatomy and Cell Biology, Medical University of ViennaDivision of Cell and Developmental Biology, Center for Anatomy and Cell Biology, Medical University of ViennaExpression génétique microbienne, Université Paris Cité, CNRS, Institut de biologie physico-chimiqueExpression génétique microbienne, Université Paris Cité, CNRS, Institut de biologie physico-chimiqueDivision of Cell and Developmental Biology, Center for Anatomy and Cell Biology, Medical University of ViennaExpression génétique microbienne, Université Paris Cité, CNRS, Institut de biologie physico-chimiqueAbstract 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.https://doi.org/10.1038/s41467-024-53777-2 |
| spellingShingle | Allegra Mboukou Vinod Rajendra Serafina Messmer Therese C. Mandl Marjorie Catala Carine Tisné Michael F. Jantsch Pierre Barraud Dimerization of ADAR1 modulates site-specificity of RNA editing Nature Communications |
| title | Dimerization of ADAR1 modulates site-specificity of RNA editing |
| title_full | Dimerization of ADAR1 modulates site-specificity of RNA editing |
| title_fullStr | Dimerization of ADAR1 modulates site-specificity of RNA editing |
| title_full_unstemmed | Dimerization of ADAR1 modulates site-specificity of RNA editing |
| title_short | Dimerization of ADAR1 modulates site-specificity of RNA editing |
| title_sort | dimerization of adar1 modulates site specificity of rna editing |
| url | https://doi.org/10.1038/s41467-024-53777-2 |
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