Rescuing dicer defects via inhibition of an anti-dicing nuclease

Cell Rep. 2014 Nov 20;9(4):1471-81. doi: 10.1016/j.celrep.2014.10.021.

Abstract

Genetic defects in the microRNA (miRNA) generating enzyme, dicer, are increasingly linked to disease. Loss of miRNA in dicer deficiency is thought to be due to loss of miRNA-generating activity. Here, we demonstrate a catabolic mechanism driving miRNA depletion in dicer deficiency. We developed a Dicer-antagonist assay revealing a pre-miRNA degrading enzyme that competes with pre-miRNA processing. We purified this pre-miRNA degrading activity using an unbiased chromatographic procedure and identified the ribonuclease complex Translin/Trax (TN/TX). In wild-type dicer backgrounds, pre-miRNA processing was dominant. However, in dicer-deficient contexts, TN/TX broadly suppressed miRNA. These findings indicate that miRNA depletion in dicer deficiency is due to the combined loss of miRNA-generating activity and catabolic function of TN/TX. Importantly, inhibition of TN/TX mitigated loss of both miRNA and tumor suppression with dicer haploinsufficiency. These studies reveal a potentially druggable target for restoring miRNA function in cancers and emerging dicer deficiencies.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Cell Fractionation
  • Chromatography
  • DNA-Binding Proteins / antagonists & inhibitors*
  • DNA-Binding Proteins / metabolism
  • HCT116 Cells
  • Haploinsufficiency
  • HeLa Cells
  • Humans
  • Mice, Inbred C57BL
  • MicroRNAs / metabolism
  • Molecular Sequence Data
  • RNA Precursors / metabolism
  • RNA Processing, Post-Transcriptional
  • RNA Stability
  • RNA-Binding Proteins / antagonists & inhibitors*
  • RNA-Binding Proteins / metabolism
  • Ribonuclease III / metabolism*

Substances

  • DNA-Binding Proteins
  • MicroRNAs
  • RNA Precursors
  • RNA-Binding Proteins
  • TSN protein, human
  • Tsn protein, mouse
  • trans-activation responsive RNA-binding protein
  • Ribonuclease III