An alternative miRISC targets a cancer-associated coding sequence mutation in FOXL2open access
- Authors
- Shin, Eunkyoung; Jin, Hanyong; Suh, Dae-Shik; Luo, Yongyang; Ha, Hye-Jeong; Kim, Tae Heon; Hahn, Yoonsoo; Hyun, Seogang; Lee, Kangseok; Bae, Jeehyeon
- Issue Date
- Dec-2020
- Publisher
- Nature Publishing Group
- Keywords
- allelic imbalance; Argonaute3; DHX9; metastasis; miR-1236
- Citation
- The EMBO Journal, v.39, no.24
- Journal Title
- The EMBO Journal
- Volume
- 39
- Number
- 24
- URI
- https://scholarworks.bwise.kr/cau/handle/2019.sw.cau/43769
- DOI
- 10.15252/embj.2020104719
- ISSN
- 0261-4189
1460-2075
- 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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Collections - College of Pharmacy > School of Pharmacy > 1. Journal Articles
- College of Natural Sciences > Department of Life Science > 1. Journal Articles
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