Cis- and trans-regulations of pre-mRNA splicing by RNA editing enzymes influence cancer development

Sze Jing Tang, Haoqing Shen, Omer An, HuiQi Hong, Jia Li, Yangyang Song, Jian Han, Daryl Jin Tai Tay, Vanessa Hui En Ng, Fernando Bellido Molias, Ka Wai Leong, Priyankaa Pitcheshwar, Henry Yang and Leilei Chen ()
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Sze Jing Tang: National University of Singapore
Haoqing Shen: National University of Singapore
Omer An: National University of Singapore
HuiQi Hong: National University of Singapore
Jia Li: National University of Singapore
Yangyang Song: 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
Ka Wai Leong: National University of Singapore
Priyankaa Pitcheshwar: National University of Singapore
Henry Yang: National University of Singapore
Leilei Chen: National University of Singapore

Nature Communications, 2020, vol. 11, issue 1, 1-17

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-14621-5

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