title: Rescuing dicer defects via inhibition of an anti-dicing nuclease.
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.
authors.forename: Ken
authors.initials: K
authors.lastname: Asada
authors.forename: Emanuele
authors.initials: E
authors.lastname: Canestrari
authors.forename: Xiuping
authors.initials: X
authors.lastname: Fu
authors.forename: Zhi
authors.initials: Z
authors.lastname: Li
authors.forename: Edward
authors.initials: E
authors.lastname: Makowski
authors.forename: Yen-Ching
authors.initials: YC
authors.lastname: Wu
authors.forename: Jeffrey K
authors.initials: JK
authors.lastname: Mito
authors.forename: David G
authors.initials: DG
authors.lastname: Kirsch
authors.forename: Jay
authors.initials: J
authors.lastname: Baraban
authors.forename: Zain
authors.initials: Z
authors.lastname: Paroo
mesh_terms: D000818:Animals; D001483:Base Sequence; D002458:Cell Fractionation; D002845:Chromatography; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D045325:HCT116 Cells; D057895:Haploinsufficiency; D006367:HeLa Cells; D006801:Humans; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000378:metabolism; D008969:Molecular Sequence Data; D012322:RNA Precursors / Q000378:metabolism; D012323:RNA Processing, Post-Transcriptional; D020871:RNA Stability; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D043244:Ribonuclease III / Q000378:metabolism*; D000099253:Trans-Activation Responsive RNA-Binding Protein
chemical_list: D004268:DNA-Binding Proteins; D035683:MicroRNAs; D012322:RNA Precursors; D016601:RNA-Binding Proteins; D043244:Ribonuclease III; D000099253:Trans-Activation Responsive RNA-Binding Protein; C095563:TSN protein, human; C498303:Tsn protein, mouse