An alternative miRISC targets a cancer-associated coding sequence mutation in FOXL2.

The EMBO Journal
Eunkyoung ShinJeehyeon Bae

Abstract

Recent evidence suggests that animal microRNAs (miRNAs) can target coding sequences (CDSs); however, the pathophysiological importance of such targeting remains unknown. Here, we show that a somatic heterozygous missense mutation (c.402C>G; p.C134W) in FOXL2, a feature shared by virtually all adult-type granulosa cell tumors (AGCTs), introduces a target site for miR-1236, which causes haploinsufficiency of the tumor-suppressor FOXL2. This miR-1236-mediated selective degradation of the variant FOXL2 mRNA is preferentially conducted by a distinct miRNA-loaded RNA-induced silencing complex (miRISC) directed by the Argonaute3 (AGO3) and DHX9 proteins. In both patients and a mouse model of AGCT, abundance of the inversely regulated variant FOXL2 with miR-1236 levels is highly correlated with malignant features of AGCT. Our study provides a molecular basis for understanding the conserved FOXL2 CDS mutation-mediated etiology of AGCT, revealing the existence of a previously unidentified mechanism of miRNA-targeting disease-associated mutations in the CDS by forming a non-canonical miRISC.

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Citations

Aug 17, 2021·The EMBO Journal·Eunkyoung ShinJeehyeon Bae
Aug 3, 2021·The Journal of Pathology·Jessica A PilsworthReiner A Veitia
Nov 3, 2021·Wiley Interdisciplinary Reviews. RNA·Pierre-Marc Frédérick, Martin J Simard
Oct 24, 2021·The Journal of Pathology·Peter J FullerSimon Chu

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Methods Mentioned

BETA
ubiquitination
transfection
PCR
immunoprecipitation
pulldown
immunoprecipitations
flow cytometry
xenograft
Illumina Sequencing
PCRs

Software Mentioned

Quantity One
SAS
OptiQuant
PyroMark Q48
MultiExperiment Viewer ( MeV
SigmaPlot

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