Rescuing dicer Defects via Inhibition of an Anti-Dicing Nuclease

Ken Asada, Emanuele Canestrari, Xiuping Fu, Zhi Li, Edward Makowski, Yen Ching Wu, Jeffrey K. Mito, David G. Kirsch, Jay Baraban, Zain Paroo

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

Genetic defects in the microRNA (miRNA) generating enzyme, dicer, are increasingly linked to disease. Loss of miRNA in dicer deficiency is thought to bedue 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.

Original languageEnglish (US)
Pages (from-to)1471-1481
Number of pages11
JournalCell Reports
Volume9
Issue number4
DOIs
StatePublished - Nov 20 2014

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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