Project name: AGO-bound Mature miRNAs with an Exposed 3’ end are Oligo-uridylated by TUTs and Subsequently Degraded by DIS3L2

Description: microRNAs (miRNAs) associating 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 oligo-uridylating 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 are targeted by this machinery presumably due to target-directed miRNA degradation.Overall design: HEK293T cells and various KO cells with or without ectopic expression of miRNAs were subjected miRNA-Seq and isomiR profile analyses.

Data type: Transcriptome or Gene expression

Sample scope: Multiisolate

Relevance: Medical

Last updated: 2019-10-29