Tissue-selective restriction of RNA editing of CaV1.3 by splicing factor SRSF9

• Published in: Nucleic acids research Vol. 46; no. 14; pp. 7323 - 7338
• Main Authors: Huang, Hua, Kapeli, Katannya, Jin, Wenhao, Wong, Yuk Peng, Arumugam, Thiruma Valavan, Koh, Joanne Huifen, Srimasorn, Sumitra, Mallilankaraman, Karthik, Chua, John Jia En, Yeo, Gene W, Soong, Tuck Wah
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 21.08.2018
• Subjects: Adenosine Deaminase - genetics; Adenosine Deaminase - metabolism; Animals; Base Sequence; Calcium Channels, L-Type - genetics; Calcium Channels, L-Type - metabolism; Cell Line, Tumor; Cells, Cultured; Gene Expression Regulation; HEK293 Cells; Humans; Kidney - metabolism; Mice, Inbred C57BL; Organ Specificity - genetics; Rats; RNA and RNA-protein complexes; RNA Editing; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; Serine-Arginine Splicing Factors - genetics; Serine-Arginine Splicing Factors - metabolism
• ISSN: 0305-1048; 1362-4962; 1362-4962
• DOI: 10.1093/nar/gky348

Abstract Adenosine DeAminases acting on RNA (ADAR) catalyzes adenosine-to-inosine (A-to-I) conversion within RNA duplex structures. While A-to-I editing is often dynamically regulated in a spatial-temporal manner, the mechanisms underlying its tissue-selective restriction remain elusive. We have previously reported that transcripts of voltage-gated calcium channel CaV1.3 are subject to brain-selective A-to-I RNA editing by ADAR2. Here, we show that editing of CaV1.3 mRNA is dependent on a 40 bp RNA duplex formed between exon 41 and an evolutionarily conserved editing site complementary sequence (ECS) located within the preceding intron. Heterologous expression of a mouse minigene that contained the ECS, intermediate intronic sequence and exon 41 with ADAR2 yielded robust editing. Interestingly, editing of CaV1.3 was potently inhibited by serine/arginine-rich splicing factor 9 (SRSF9). Mechanistically, the inhibitory effect of SRSF9 required direct RNA interaction. Selective down-regulation of SRSF9 in neurons provides a basis for the neuron-specific editing of CaV1.3 transcripts.