1. Cis- and trans-regulations of pre-mRNA splicing by RNA editing enzymes influence cancer development.
- Author
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Tang SJ, Shen H, An O, Hong H, Li J, Song Y, Han J, Tay DJT, Ng VHE, Bellido Molias F, Leong KW, Pitcheshwar P, Yang H, and Chen L
- Subjects
- Adenosine Deaminase genetics, Alternative Splicing, Animals, Carrier Proteins genetics, Cell Line, Tumor, Exons, Gene Expression Regulation, Neoplastic, Humans, Membrane Proteins genetics, Mice, Inbred NOD, Nonsense Mediated mRNA Decay, RNA Editing, RNA Splice Sites, RNA Splicing, RNA, Double-Stranded genetics, RNA, Double-Stranded metabolism, RNA, Messenger genetics, RNA-Binding Proteins genetics, Serine-Arginine Splicing Factors genetics, Splicing Factor U2AF genetics, Adenosine Deaminase metabolism, Neoplasms genetics, RNA Precursors genetics, RNA-Binding Proteins metabolism
- Abstract
RNA editing and splicing are the two major processes that dynamically regulate human transcriptome diversity. Despite growing evidence of crosstalk between RNA editing enzymes (mainly ADAR1) and splicing machineries, detailed mechanistic explanations and their biological importance in diseases, such as cancer are still lacking. Herein, we identify approximately a hundred high-confidence splicing events altered by ADAR1 and/or ADAR2, and ADAR1 or ADAR2 protein can regulate cassette exons in both directions. We unravel a binding tendency of ADARs to dsRNAs that involves GA-rich sequences for editing and splicing regulation. ADAR1 edits an intronic splicing silencer, leading to recruitment of SRSF7 and repression of exon inclusion. We also present a mechanism through which ADAR2 binds to dsRNA formed between GA-rich sequences and polypyrimidine (Py)-tract and precludes access of U2AF65 to 3' splice site. Furthermore, we find these ADARs-regulated splicing changes per se influence tumorigenesis, not merely byproducts of ADARs editing and binding.
- Published
- 2020
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