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Dissecting the basis for differential substrate specificity of ADAR1 and ADAR2
Marlon S Zambrano-Mila1, Monika Witzenberger1, Zohar Rosenwasser2
1Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, 7630031, Israel.
Nature Communications
|December 11, 2023
Summary
Adenosine deaminases ADAR1 and ADAR2 show distinct RNA structure preferences, influencing their substrate selectivity. Understanding these differences can improve the design of targeted RNA therapeutics.
Area of Science:
- Biochemistry
- Molecular Biology
- Genetics
Background:
- Adenosine deaminases acting on RNA (ADARs) modify the transcriptome.
- ADAR1 and ADAR2 exhibit substrate specificity, but determinants remain unclear.
Purpose of the Study:
- Investigate how RNA secondary structure influences ADAR1 vs. ADAR2 substrate selectivity.
- Determine the molecular basis for differential enzyme offsets.
- Explore applications in therapeutic design.
Main Methods:
- Systematic probing of thousands of synthetic RNA sequences.
- Transfection into cell lines expressing exclusively ADAR1 or ADAR2.
- Mutagenesis, domain-swaps, and analysis of ADAR homologs.
Main Results:
- Both ADAR1 and ADAR2 induce strand-specific editing with distinct offsets (-26 nt for ADAR2, -35 nt for ADAR1) relative to structural disruptions.
- Differential RNA binding domain (RBD) architecture underlies these offset differences.
- Offset-enhanced editing improves ADAR2-recruiting therapeutic design.
Conclusions:
- RNA secondary structure significantly modulates ADAR1 and ADAR2 selectivity.
- The RNA binding domain architecture is critical for differential enzyme offsets.
- Targeted therapeutic strategies can leverage ADAR enzyme specificities for enhanced efficacy.
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