An RNA editing/dsRNA binding-independent gene regulatory mechanism of ADARs and its clinical implication in cancer

Abstract

Adenosine-to-inosine (A-to-I) RNA editing, catalyzed by Adenosine DeAminases acting on double-stranded RNA(dsRNA) (ADAR), occurs predominantly in the 3′ untranslated regions (3′UTRs) of spliced mRNA. Here we uncover an unanticipated link between ADARs (ADAR1 and ADAR2) and the expression of target genes undergoing extensive 3′UTR editing. Using METTL7A (Methyltransferase Like 7A), a novel tumor suppressor gene with multiple editing sites at its 3′UTR, we demonstrate that its expression could be repressed by ADARs beyond their RNA editing and double-stranded RNA (dsRNA) binding functions. ADARs interact with Dicer to augment the processing of pre-miR-27a to mature miR-27a. Consequently, mature miR-27a targets the METTL7A 3′UTR to repress its expression level. In sum, our study unveils that the extensive 3′UTR editing of METTL7A is merely a footprint of ADAR binding, and there are a subset of target genes that are equivalently regulated by ADAR1 and ADAR2 through their non-canonical RNA editing and dsRNA binding-independent functions, albeit maybe less common. The functional significance of ADARs is much more diverse than previously appreciated and this gene regulatory function of ADARs is most likely to be of high biological importance beyond the best-studied editing function. This non-editing side of ADARs opens another door to target cancer.

ADAR1-mediated RNA-editing of 3′UTRs in breast cancer

“…Further, we compared the A to G(I) changes in the 571 UTRs in tumor and normal tissues. Remarkably, 114 UTR’s presented an increased editing number of editing site in the tumoral samples, compared to the normal samples analyzed (with at least 1.25 > FC), most of them consisting of 3′ UTRs (110/114), showing an increased level or number of edited sites of previously reported ADAR1 targets, including APOL1 [ 23 ], MDM2 [ 21 ], MTDH and TNFAIP8L1 [ 24 ] (shown in Additional file 4 ). Interestingly, tumors show a significant increase number of edited sites at 3′UTRs of several important transcripts involved in gene expression related pathways such as metabolism of non-coding RNAs, generic transcription pathway, snRNP assembly and cell cycle, DNA damage response and DNA replication related pathways showing an increased number of edited sites on key mRNAs associated to that signaling pathways, such as ATM , GINS4 , and POLH mRNAs (Fig.…”

“…Moreover, 3′UTRs allow RNA/RNA interactions that function as an important regulatory mechanism for the regulation of mRNA expression. Recently, Qi et al (2017) [ 24 ] reported that RNA editing in 3′UTRs undergo expression changes independently of their editing levels and ADAR dsRNA binding capabilities, suggesting that ADAR1 could regulate the expression and/or stability of the editing target by a growing number of different mechanisms.…”

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

“…To understand whether ADARs regulate CCDC15-ex9 and RELL2-ex3 inclusion through or beyond their editing functions, we generated different ADAR1/2 mutants devoid of either enzymatic activity (DeAD mutants) 39 or dsRNA-binding capability (EAA mutants) 40,41 . In both HEK293T and EC109 cells, CCDC15-ex9 inclusion was repressed by wild-type ADAR1; intriguingly, it was also repressed by wild-type ADAR2 ( Fig.…”

Deduction of novel genes potentially involved in hypoxic AC16 human cardiomyocytes using next-generation sequencing and bioinformatics approaches

“…Decreased expression of TFRC has been associated with reduced pulmonary smooth muscle cell proliferation in hypoxia ( 60 ). METTL7A has been recognized as a novel tumor suppressor gene ( 61 ). The actual role of the downregulation of METTL7A in CMs and cardiac microvascular endothelial cells in response to hypoxia remains uncertain and requires further investigation.…”