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

TY - JOUR

T1 - AGO-bound mature miRNAs are oligouridylated by TUTs and subsequently degraded by DIS3L2

AU - Yang, Acong

AU - Shao, Tie Juan

AU - Bofill-De Ros, Xavier

AU - Lian, Chuanjiang

AU - Villanueva, Patricia

AU - Dai, Lisheng

AU - Gu, Shuo

N1 - Publisher Copyright: © 2020, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.

PY - 2020/12/1

Y1 - 2020/12/1

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85085704908

U2 - 10.1038/s41467-020-16533-w

DO - 10.1038/s41467-020-16533-w

M3 - Journal article

C2 - 32488030

AN - SCOPUS:85085704908

SN - 2041-1723

VL - 11

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 2765

ER -