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Rescuing dicer Defects via Inhibition of an Anti-Dicing Nuclease
- Source :
- Cell Reports, Vol 9, Iss 4, Pp 1471-1481 (2014)
- Publication Year :
- 2014
- Publisher :
- Elsevier, 2014.
-
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.
- Subjects :
- Biology (General)
QH301-705.5
Subjects
Details
- Language :
- English
- ISSN :
- 22111247
- Volume :
- 9
- Issue :
- 4
- Database :
- Directory of Open Access Journals
- Journal :
- Cell Reports
- Publication Type :
- Academic Journal
- Accession number :
- edsdoj.82e108c3c5f744ed8351da295b491bab
- Document Type :
- article
- Full Text :
- https://doi.org/10.1016/j.celrep.2014.10.021