| Autor: |
Asada, Ken, Canestrari, Emanuele, Fu, Xiuping, Li, Zhi, Makowski, Edward, Wu, Yen-Ching, Mito, Jeffrey K., Kirsch, David G., Baraban, Jay, Paroo, Zain |
| Zdroj: |
Cell Reports; November 2014, Vol. 9 Issue: 4 p1471-1481, 11p |
| Abstrakt: |
Genetic defects in the microRNA (miRNA) generating enzyme, dicer, are increasingly linked to disease. Loss of miRNA in dicerdeficiency is thought to be due to loss of miRNA-generating activity. Here, we demonstrate a catabolic mechanism driving miRNA depletion in dicerdeficiency. 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 dicerbackgrounds, pre-miRNA processing was dominant. However, in dicer-deficient contexts, TN/TX broadly suppressed miRNA. These findings indicate that miRNA depletion in dicerdeficiency 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 dicerhaploinsufficiency. These studies reveal a potentially druggable target for restoring miRNA function in cancers and emerging dicerdeficiencies. |
| Databáze: |
Supplemental Index |
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