Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.26.9 (ribonuclease)
 6,589 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Rescuing dicer defects via inhibition of an anti-dicing nuclease. 2545 13

Despite immense promise, development of microRNA (miRNA) therapeutics remains limited by pharmacodynamic challenges that have hindered progress of related oligonucleotide-based technologies. Recent discovery of enzymes that mediate miRNA metabolism represent potential pharmacological targets for directing miRNA function, circumventing barriers associated with oligonucleotides. We previously identified the Translin/Trax (TN/TX) ribonuclease complex as a pre-miRNA degrading enzyme that competes with pre-miRNA processing by Dicer. Here, we establish a high-throughput TN/TX assay and screened 2320 drug and natural product compounds for inhibitors of TN/TX. Secondary analyses demonstrate small molecule mediated inhibition of pre-miRNA degradation by TN/TX and enhanced miRNA processing by Dicer. This application of traditional enzyme-inhibitor pharmacology to the miRNA pathway establishes a druggable target for rescuing global miRNA defects, providing an important complement to current approaches towards miRNA therapeutics. More broadly, demonstrating feasibility of pharmacological targeting of the 'ribonucleome' is particularly important given emerging classes of regulatory RNA and growing understanding of their importance in health and disease.
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PMID:A druggable target for rescuing microRNA defects. 2764 67

Dicer-deficient cancers have poor prognoses, which is linked to the degradation of tumour-suppressing miRNA precursors by the Translin-Trax (Tn-Tx) ribonuclease. Inhibition of Tn-Tx potentially offers a new therapeutic intervention point. However, Tn-Tx functions in an array of biological processes, and here we consider how this complexity could influence therapeutic design strategies.
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PMID:Translin-Trax: Considerations for Oncological Therapeutic Targeting. 3246