期刊
NATURE COMMUNICATIONS
卷 13, 期 1, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41467-022-29138-2
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资金
- National Research Foundation Singapore
- Singapore Ministry of Education under its Research Centres of Excellence initiative
- Singapore Ministry of Education's Tier 2 Grants [MOE2018-T2-1-005, MOE2019-T2-2-008]
- NMRC Clinician Scientist-Individual Research Grant (CS-IRG) [MOH-000214]
- Singapore Ministry of Education's Tier 3 Grants [MOE2014-T3-1-006]
This study demonstrates that ADARs play a significant role in regulating the circular transcriptome. ADARs can stabilize or destabilize circRNA secondary structures through editing, and also enhance the binding of RNA-binding proteins. These ADARs-regulated circRNAs are widely expressed in various cancers and have functional relevance to tumorigenesis.
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.
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