Rescuing dicer defects via inhibition of an anti-dicing nuclease.

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Asada, K; Canestrari, E; Fu, X; Li, Z; Makowski, E; Wu, Y-C; Mito, JK; Kirsch, DG; Baraban, J; Paroo, Z

Published Date

  • November 20, 2014

Published In

Volume / Issue

  • 9 / 4

Start / End Page

  • 1471 - 1481

PubMed ID

  • 25457613

Pubmed Central ID

  • 25457613

Electronic International Standard Serial Number (EISSN)

  • 2211-1247

Digital Object Identifier (DOI)

  • 10.1016/j.celrep.2014.10.021

Language

  • eng

Conference Location

  • United States