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DICER1 platform domain missense variants inhibit miRNA biogenesis and lead to tumor susceptibility

Dylan Pelletier1,2,3, Anne-Laure Chong1,2, Mona Wu1,2

  • 1Department of Human Genetics, Medicine, McGill University, Montreal, QC, Canada.

NAR Cancer
|June 19, 2023
PubMed

Insights

Germline DICER1 variants in the Platform domain prevent mature miRNA production, impairing gene silencing and causing DICER1 tumor predisposition syndrome (DTPS). This contrasts with other variants affecting cleavage, highlighting a unique mechanism of disease.

Area of Science:

  • Molecular Biology
  • Genetics
  • Cancer Research

Background:

  • DICER1 is crucial for microRNA (miRNA) biogenesis, processing precursor miRNAs (pre-miRNAs) into mature miRNAs.
  • Germline pathogenic variants (GPVs) in DICER1 cause DICER1 tumor predisposition syndrome (DTPS), a childhood cancer susceptibility disorder.
  • Canonical DTPS arises from nonsense/frameshift DICER1 variants requiring a second somatic hit affecting the RNase IIIb domain.

Purpose of the Study:

  • To investigate the impact of germline DICER1 missense variants in the Platform domain on miRNA biogenesis and gene silencing.
  • To elucidate the mechanism by which these Platform domain variants contribute to DTPS.

Main Methods:

  • Functional assays were used to assess the production of mature miRNAs by DICER1 proteins with Platform domain variants.
  • Experiments were conducted to evaluate miRNA-mediated gene silencing.
  • Binding assays were performed to determine if Platform variants affect pre-miRNA binding.

Main Results:

  • Four Platform domain variants were found to abolish mature miRNA production.
  • These variants consequently impaired miRNA-mediated gene silencing.
  • Unlike variants affecting cleavage, Platform variants prevent DICER1 from binding to pre-miRNA stem-loops.

Conclusions:

  • Germline DICER1 Platform domain variants represent a unique class of GPVs causing DTPS.
  • These variants disrupt miRNA biogenesis by preventing substrate binding, rather than altering cleavage activity.
  • This study provides novel insights into the molecular mechanisms underlying DICER1-related tumor predisposition.

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