Abstract

MicroRNAs (miRNAs) associated with Argonaute proteins (AGOs) regulate gene expression in mammals. miRNA 3’ ends are subject to frequent sequence modifications, which have been proposed to affect miRNA stability. However, the underlying mechanism is not well understood. Here, by genetic and biochemical studies as well as deep sequencing analyses, we find that AGO mutations disrupting miRNA 3’ binding are sufficient to trigger extensive miRNA 3’ modifications in HEK293T cells and in cancer patients. Comparing these modifications in TUT4, TUT7 and DIS3L2 knockout cells, we find that TUT7 is more robust than TUT4 in oligouridylating mature miRNAs, which in turn leads to their degradation by the DIS3L2 exonuclease. Our findings indicate a decay machinery removing AGO-associated miRNAs with an exposed 3’ end. A set of endogenous miRNAs including miR-7, miR-222 and miR-769 are targeted by this machinery presumably due to target-directed miRNA degradation.

3′ end of microRNAs binds to the PAZ domain of Argonaute (AGO) proteins. Here the authors show that terminal nucleotidyltransferases TUT4/7 and exonuclease DIS3L2 induce tailing and decay of 3’ end exposed-microRNAs in AGO PAZ mutant expressing- or cancer cells.

Details

Title
AGO-bound mature miRNAs are oligouridylated by TUTs and subsequently degraded by DIS3L2
Author
Yang Acong 1   VIAFID ORCID Logo  ; Tie-Juan, Shao 2 ; Bofill-De, Ros Xavier 1   VIAFID ORCID Logo  ; Lian Chuanjiang 3 ; Villanueva, Patricia 1 ; Dai Lisheng 1 ; Gu Shuo 1   VIAFID ORCID Logo 

1  Center for Cancer Research, National Cancer Institute, RNA Mediated Gene Regulation Section; RNA Biology Laboratory, Frederick, USA (GRID:grid.417768.b) (ISNI:0000 0004 0483 9129) 
2  Center for Cancer Research, National Cancer Institute, RNA Mediated Gene Regulation Section; RNA Biology Laboratory, Frederick, USA (GRID:grid.417768.b) (ISNI:0000 0004 0483 9129); Zhejiang Chinese Medical University, School of Basic Medicine, Hangzhou, China (GRID:grid.268505.c) (ISNI:0000 0000 8744 8924) 
3  Center for Cancer Research, National Cancer Institute, RNA Mediated Gene Regulation Section; RNA Biology Laboratory, Frederick, USA (GRID:grid.417768.b) (ISNI:0000 0004 0483 9129); Chinese Academy of Agricultural Sciences, State Key Laboratory of Veterinary Biotechnology and Heilongjiang Province Key Laboratory for Laboratory Animal and Comparative Medicine, Harbin Veterinary Research Institute, Harbin, China (GRID:grid.410727.7) (ISNI:0000 0001 0526 1937) 
Publication year
2020
Publication date
2020
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-020-16533-w
ProQuest document ID
2408813472
Copyright
© This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply 2020. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.