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AGO-bound mature miRNAs are oligouridylated by TUTs and subsequently degraded by DIS3L2

Yang, Acong, Shao, Tie-Juan, Bofill-De Ros, Xavier, Lian, Chuanjiang, Villanueva, Patricia, Dai, Lisheng, Gu, Shuo·2020·Nature Communications
DOI 10.1038/s41467-020-16533-wPMC PMC7265490
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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.

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  • TDMD may promote dissociation of the 3' end of the miRNA from the Argonaute protein, thereby exposing the 3' end to modifications that lead to miRNA degradation.

    “TDMD may promote dissociation of the 3′ end of the miRNA from the Argonaute protein, thereby exposing the 3′ end to modifications that lead to miRNA degradation (Sheu‐Gruttadauria et al., 2019; Yang et al., 2020).”

    From microRNA strand selection: Unwinding the rules (2021) · cites this paper as Yang et al., 2020

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Authors
Yang, A., Shao, T.-J., Bofill-De Ros, X., Lian, C., Villanueva, P., Dai, L., & Gu, S.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2020-06-02
Volume
11
Issue
1
ISSN
2041-1723
DOI
10.1038/s41467-020-16533-w
PMC
PMC7265490
Cited by
76
References
0
Language
en
Licence
Funders
U.S. Department of Health & Human Services | NIH | National Cancer Institute (ZIA BC 011566)

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