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Nat. Struct. Mol. Biol., 04 November 2025 | https://doi.org/10.1038/s41594-025-01701-7
Human DICER1 hotspot mutation induces both loss and gain of miRNA function
David Jee1,2, Seungjae Lee1,2, Dapeng Yang1, Robert Rickert1, Renfu Shang1, Danwei Huangfu1 & Eric C. Lai1
1Developmental Biology Program, Sloan Kettering Institute, New York, NY, USA.
2These authors contributed equally: David Jee, Seungjae Lee.
Corresponding author
Correspondence to Eric C. Lai.
1Developmental Biology Program, Sloan Kettering Institute, New York, NY, USA.
2These authors contributed equally: David Jee, Seungjae Lee.
Corresponding author
Correspondence to Eric C. Lai.
Abstract
The core miRNA biogenesis enzyme DICER1 sustains recurrent mutations in cancer that compromise its RNase IIIb domain, which cleaves 5p arms of precursor microRNA hairpins. However, the lack of knock-in models has limited fuller understanding. Here, we generated DICER1-knockout and DICER1S1344L (homozygous and hemizygous) human embryonic stem cells; the latter is a noncatalytic substitution in RNase IIIa that impairs RNase IIIb activity. DICER1 knockouts lack canonical miRNAs, while S1344L induces two trends: ablation of miRNA-5p strands and selective changes in miRNA-3p strands. Curiously, we recognized directional upregulation of miRNA-3p passenger strands, indicating a broad strand switch. We used multiple in vitro assays to show 3p-arm-nicked pre-miRNAs preferentially load miRNA-3p species into Argonaute, compared to corresponding duplexes. Moreover, activity assays, RNA-sequencing data and Argonaute mRNA profiling confirm that these confer increased repression capacity. These data expand the molecular consequences of DICER1 hotspot mutations in cancer.
논문정보
- Research article
- 2025년 11월 (BRIC 등록일 2025-11-05)
- 국외 연구진
- 생명과학 > 분자생물학
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