RRC ID 66867
Author Shin E, Jin H, Suh DS, Luo Y, Ha HJ, Kim TH, Hahn Y, Hyun S, Lee K, Bae J.
Title An alternative miRISC targets a cancer-associated coding sequence mutation in FOXL2.
Journal EMBO J
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.
Volume 39(24)
Pages e104719
Published 2020-12-15
DOI 10.15252/embj.2020104719
PMID 33215742
PMC PMC7737606
MeSH Allelic Imbalance Animals Apoptosis Argonaute Proteins / genetics Argonaute Proteins / metabolism Cell Death / physiology DEAD-box RNA Helicases / genetics DEAD-box RNA Helicases / metabolism Forkhead Box Protein L2 / genetics* Forkhead Box Protein L2 / metabolism* Gene Expression Regulation, Neoplastic Gene Knockout Techniques Granulosa Cell Tumor / genetics* Granulosa Cell Tumor / pathology HEK293 Cells Humans Mice Mice, Knockout MicroRNAs / genetics MicroRNAs / metabolism* Mutation* Mutation, Missense Neoplasm Proteins / genetics Neoplasm Proteins / metabolism Open Reading Frames* RNA, Messenger / metabolism Transcriptome
IF 9.889
Human and Animal Cells KGN(RCB1154)