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Mol Cell. 2019 Aug 8;75(3):511-522.e4. doi: 10.1016/j.molcel.2019.05.014. Epub 2019 Jun 6.

3' Uridylation Confers miRNAs with Non-canonical Target Repertoires.

Author information

1
RNA Mediated Gene Regulation Section, RNA Biology Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA.
2
RNA Mediated Gene Regulation Section, RNA Biology Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA; School of Basic Medicine, Zhejiang Chinese Medical University, Hangzhou 310053, China.
3
RNA Mediated Gene Regulation Section, RNA Biology Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA. Electronic address: shuo.gu@nih.gov.

Abstract

Many microRNAs (miRNAs) exist alongside abundant miRNA isoforms (isomiRs), most of which arise from post-maturation sequence modifications such as 3' uridylation. However, the ways in which these sequence modifications affect miRNA function remain poorly understood. Here, using human miR-27a in cell lines as a model, we discovered that a nonfunctional target site unable to base-pair extensively with the miRNA seed sequence can regain function when an upstream adenosine is able to base-pair with a post-transcriptionally added uridine in the miR-27a tail. This tail-U-mediated repression (TUMR) is abolished in cells lacking the uridylation enzymes TUT4 and TUT7, indicating that uridylation alters miRNA function by modulating target recognition. We identified a set of non-canonical targets in human cells that are specifically regulated by uridylated miR-27a. We provide evidence that TUMR expands the targets of other endogenous miRNAs. Our study reveals a function of uridylated isomiRs in regulating non-canonical miRNA targets.

KEYWORDS:

isomiRs; miR-27a; miRNA; noncanonical target; uridylation

PMID:
31178353
PMCID:
PMC6688926
[Available on 2020-08-08]
DOI:
10.1016/j.molcel.2019.05.014

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