Affiliations
1Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
2Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
3Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
4Division of Colorectal Surgery, University Surgical Cluster, National University Health System, Singapore, Singapore.
5NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
6Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore. polly_chen@nus.edu.sg.
7Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. polly_chen@nus.edu.sg.
8NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. polly_chen@nus.edu.sg.
Abstract
Circular RNAs (circRNAs) are produced by head-to-tail back-splicing which is mainly facilitated by base-pairing of reverse complementary matches (RCMs) in circRNA flanking introns. Adenosine deaminases acting on RNA (ADARs) are known to bind double-stranded RNAs for adenosine to inosine (A-to-I) RNA editing. Here we characterize ADARs as potent regulators of circular transcriptome by identifying over a thousand of circRNAs regulated by ADARs in a bidirectional manner through and beyond their editing function. We find that editing can stabilize or destabilize secondary structures formed between RCMs via correcting A:C mismatches to I(G)-C pairs or creating I(G).U wobble pairs, respectively. We provide experimental evidence that editing also favors the binding of RNA-binding proteins such as PTBP1 to regulate back-splicing. These ADARs-regulated circRNAs which are ubiquitously expressed in multiple types of cancers, demonstrate high functional relevance to cancer. Our findings support a hitherto unappreciated bidirectional regulation of circular transcriptome by ADARs and highlight the complexity of cross-talk in RNA processing and its contributions to tumorigenesis.
© 2022. The Author(s).
PMID: 35314703 DOI: 10.1038/s41467-022-29138-2