RT Journal Article
SR Electronic
T1 An RNA editing/binding-independent gene regulatory mechanism of ADARs and its clinical implication in cancer
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 062778
DO 10.1101/062778
A1 Lihua Qi
A1 Yangyang Song
A1 Tim Hon Man Chan
A1 Henry Yang
A1 Chi Ho Lin
A1 Daryl Jin Tai Tay
A1 HuiQi Hong
A1 Jaymie Siqi Lin
A1 Vanessa Hui En Ng
A1 Julien Jean Pierre Maury
A1 Daniel G. Tenen
A1 Leilei Chen
YR 2016
UL http://biorxiv.org/content/early/2016/07/08/062778.abstract
AB Adenosine-to-inosine (A-to-I) editing, catalysed by Adenosine DeAminases acting on double-stranded RNA (dsRNA) (ADAR), occurs predominantly in the 3’ untranslated regions (3’UTRs). 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 as an exemplary target gene, we demonstrate that its expression could be repressed by ADARs beyond their RNA editing and 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 is merely a footprint of ADAR binding, and is dispensable for the regulation of at least a subset of target genes. Instead, ADARs contribute to cancer progression by regulating cancer-related gene expression through their non-canonical functions independent of RNA editing and dsRNA binding. 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 higher importance than the best-studied editing function. This novel non-editing side of ADARs opens another door to target cancer. This study is timely and represents a major break-through in the field of ADAR gene regulation and cancer biology.