Deciphering the principles of the RNA editing code via large-scale systematic probing

Anna Uzonyi, Ronit Nir, Ofir Shliefer, Noam Stern-Ginossar, Yaron Antebi, Yonatan Stelzer, Erez Y. Levanon, Schraga Schwartz

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

Adenosine-to-inosine editing is catalyzed by ADAR1 at thousands of sites transcriptome-wide. Despite intense interest in ADAR1 from physiological, bioengineering, and therapeutic perspectives, the rules of ADAR1 substrate selection are poorly understood. Here, we used large-scale systematic probing of ∼2,000 synthetic constructs to explore the structure and sequence context determining editability. We uncover two structural layers determining the formation and propagation of A-to-I editing, independent of sequence. First, editing is robustly induced at fixed intervals of 35 bp upstream and 30 bp downstream of structural disruptions. Second, editing is symmetrically introduced on opposite sites on a double-stranded structure. Our findings suggest a recursive model for RNA editing, whereby the structural alteration induced by the editing at one site iteratively gives rise to the formation of an additional editing site at a fixed periodicity, serving as a basis for the propagation of editing along and across both strands of double-stranded RNA structures.

Original languageEnglish
Pages (from-to)2374-2387.e3
JournalMolecular Cell
Volume81
Issue number11
DOIs
StatePublished - 3 Jun 2021

Bibliographical note

Publisher Copyright:
© 2021 Elsevier Inc.

Keywords

  • A-to-I editing
  • ADAR1
  • RNA editing
  • adenosine
  • biotechnology
  • inosine
  • molecular biology
  • molecular genetics
  • systems biology
  • targeted editing

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