ADARs act as potent regulators of circular transcriptome in cancer

Haoqing Shen, Omer An, Xi Ren, Yangyang Song, Sze Jing Tang, Xin-Yu Ke, Jian Han, Daryl Jin Tai Tay, Vanessa Hui En Ng, Fernando Bellido Molias, Priyankaa Pitcheshwar, Ka Wai Leong, Ker-Kan Tan, Henry Yang and Leilei Chen ()
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Haoqing Shen: National University of Singapore
Omer An: National University of Singapore
Xi Ren: National University of Singapore
Yangyang Song: National University of Singapore
Sze Jing Tang: National University of Singapore
Xin-Yu Ke: National University of Singapore
Jian Han: National University of Singapore
Daryl Jin Tai Tay: National University of Singapore
Vanessa Hui En Ng: National University of Singapore
Fernando Bellido Molias: National University of Singapore
Priyankaa Pitcheshwar: National University of Singapore
Ka Wai Leong: National University of Singapore
Ker-Kan Tan: National University of Singapore
Henry Yang: National University of Singapore
Leilei Chen: National University of Singapore

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-29138-2

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