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Recognition of non-CpG repeats in Alu and ribosomal RNAs by the Z-RNA binding domain of ADAR1 induces A-Z junctions.

Nat Commun. 2021 Feb 04;12(1):793
Parker J Nichols 1 , Shaun Bevers 2 , Morkos Henen 3 , Jeffrey S Kieft 4 , Quentin Vicens 5 , Beat Vögeli 6
Parker J Nichols 1 , Shaun Bevers 2 , Morkos Henen 3 , Jeffrey S Kieft 4 , Quentin Vicens 5 , Beat Vögeli 6
+ et al

[No authors listed]

Author information
  • 1 Department of Biochemistry and Molecular Genetics, University of Colorado Denver School of Medicine, Aurora, CO, 80045, USA.
  • 2 Colorado School of Mines, Golden, CO, 80401, USA.
  • 3 Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.
  • 4 RNA BioScience Initiative, University of Colorado Denver School of Medicine, Aurora, CO, 80045, USA.
  • 5 Department of Biochemistry and Molecular Genetics, University of Colorado Denver School of Medicine, Aurora, CO, 80045, USA. quentin.vicens@cuanschutz.edu.
  • 6 Department of Biochemistry and Molecular Genetics, University of Colorado Denver School of Medicine, Aurora, CO, 80045, USA. beat.vogeli@cuanschutz.edu.

摘要


Adenosine-to-inosine (A-to-I) editing of eukaryotic cellular RNAs is essential for protection against auto-immune disorders. Editing is carried out by ADAR1, whose innate immune response-specific cytoplasmic isoform possesses a Z-DNA binding domain (Zα) of unknown function. Zα also binds to CpG repeats in RNA, which are a hallmark of Z-RNA formation. Unexpectedly, Zα has been predicted - and in some cases even shown - to bind to specific regions within mRNA and rRNA devoid of such repeats. Here, we use NMR, circular dichroism, and other biophysical approaches to demonstrate and characterize the binding of Zα to mRNA and rRNA fragments. Our results reveal a broad range of RNA sequences that bind to Zα and adopt Z-RNA conformations. Binding is accompanied by destabilization of neighboring A-form regions which is similar in character to what has been observed for B-Z-DNA junctions. The binding of Zα to non-CpG sequences is specific, cooperative and occurs with an affinity in the low micromolar range. This work allows us to propose a model for how Zα could influence the RNA binding specificity of ADAR1.