A TARBP2 mutation in human cancer impairs microRNA processing and DICER1 function

Cancer Epigenetics Laboratory, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain.
Nature Genetics (Impact Factor: 29.35). 04/2009; 41(3):365-70. DOI: 10.1038/ng.317
Source: PubMed


microRNAs (miRNAs) are small noncoding RNAs that regulate gene expression by targeting messenger RNA (mRNA) transcripts. Recently, a miRNA expression profile of human tumors has been characterized by an overall miRNA downregulation. Explanations for this observation include a failure of miRNA post-transcriptional regulation, transcriptional silencing associated with hypermethylation of CpG island promoters and miRNA transcriptional repression by oncogenic factors. Another possibility is that the enzymes and cofactors involved in miRNA processing pathways may themselves be targets of genetic disruption, further enhancing cellular transformation. However, no loss-of-function genetic alterations in the genes encoding these proteins have been reported. Here we have identified truncating mutations in TARBP2 (TAR RNA-binding protein 2), encoding an integral component of a DICER1-containing complex, in sporadic and hereditary carcinomas with microsatellite instability. The presence of TARBP2 frameshift mutations causes diminished TRBP protein expression and a defect in the processing of miRNAs. The reintroduction of TRBP in the deficient cells restores the efficient production of miRNAs and inhibits tumor growth. Most important, the TRBP impairment is associated with a destabilization of the DICER1 protein. These results provide, for a subset of human tumors, an explanation for the observed defects in the expression of mature miRNAs.

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    • "Dicer immunoprecipitation revealed that AGO2 binds to Dicer in cancer exosomes, while both are undetectable in normosomes (Figure 3J). TRBP functions as a key partner of Dicer protein and aids in its stability and in its pre-miRNA cleavage activity (Chendrimada et al., 2005; Melo et al., 2009). Dicer immunoprecipitation revealed the presence of Dicer/TRBP complex in cancer exosomes, but not in normosomes (Figure 3K). "
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    Cancer cell 11/2014; 26(5):707-21. DOI:10.1016/j.ccell.2014.09.005 · 23.52 Impact Factor
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    • "However, genetic defects of the miRNA-generating machinery represent a general mechanism. Indeed, lossof-function mutations have been reported for trbp (Melo et al., 2009), exportin-5 (Melo et al., 2010), and dicer (Hill et al., 2009; Foulkes et al., 2011; Rio Frio et al., 2011; Heravi-Moussavi et al., 2012). However, these mutations are very rare. "
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    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. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 11/2014; 9(4):1471-1481. DOI:10.1016/j.celrep.2014.10.021 · 8.36 Impact Factor
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    • "The negative correlation of miR-15b to Drosha and Ago2 hinted that Drosha and Ago2 were regulated by miR-15b. The reversed expression of miR-15b (Melo et al. 2009; Smith et al. 2010) with these key enzymes has also been observed in humans and model animals. The lower expression of miR-15b and miR-221~222 in EHL may be responsible for the higher expression of these enzymes in EHL than in LW. "
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    ABSTRACT: MicroRNA (miRNA) biogenesis is determined mainly by Drosha, Dicer and Argonaute2 (Ago2). Different breeds of pigs with vast differences in serum cortisol level demonstrate distinct profiles of hepatic miRNA expression. As yet, little is known about whether glucocorticoid contributes to the breed differences in miRNA biogenesis. Here, we used newborn Large White (LW) and Erhualian (EHL) piglets to investigate the role of glucocorticoid in breed-specific hepatic miRNA biogenesis. Erhualian piglets showing significantly higher serum cortisol level, as compared to LW, demonstrated higher hepatic expression of Drosha, Dicer and Ago2 at the protein level, but not at the mRNA level. At the post-transcriptional level, miRNAs that are predicted to target these proteins may be involved in the regulation. Hepatic expression of miR-15b and miR-222 was significantly lower in EHL piglets and was associated with higher glucocorticoid receptor binding to the respective promoter regions of miR-15b and miR-222 genes. The inhibitory effect of glucocorticoid on miR-15b and miR-222 expression was further verified in HepG2 cells, in which dexamethasone significantly downregulated the expression of primary transcripts of miR-15b and miR-222 genes. In conclusion, the higher protein content of Drosha, Dicer and Ago2 in the liver of EHL piglets is post-transcriptionally regulated, at least in part, by glucocorticoid-mediated repression of miR-15b and miR-222.
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