Article

Extensive variation in the 5'-UTR of Dicer mRNAs influences translational efficiency.

Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ont., Canada.
Biochemical and Biophysical Research Communications (Impact Factor: 2.41). 10/2005; 335(3):643-50. DOI: 10.1016/j.bbrc.2005.07.138
Source: PubMed

ABSTRACT The Dicer enzyme is a key component of the RNA interference pathway and also responsible for the processing of micro RNAs, non-coding RNA molecules which regulate the activity of mRNAs by antisense base pairing. Little is known about the structure and regulation of human Dicer mRNA. A comprehensive characterization of Dicer 5'-untranslated region (5'-UTR) RNA structure revealed important diversity within human Dicer mRNA transcripts. Three exon 1 variants were defined, some of which exhibited very restricted patterns of tissue distribution. A number of alternatively spliced 5'-leader exons were also noted, revealing the potential for complex post-transcriptional regulation. Surprisingly, this diversity all occurred within the 5'-UTR of Dicer mRNAs and did not affect the coding region. The Dicer mRNA 5'-UTR variants had profound effects on translational efficiency both in vitro and in transiently transfected cells. A number of major Dicer RNA species are inefficient substrates for the translational machinery.

0 Bookmarks
 · 
56 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The production of different types of blood cells including their formation, development, and differentiation is collectively known as haematopoiesis. Blood cells are divided into three lineages erythriod (erythrocytes), lymphoid (B and T cells), and myeloid (granulocytes, megakaryocytes, and macrophages). Haematopoiesis is a complex process regulated by several mechanisms including microRNAs (miRNAs). miRNAs are small RNAs which regulate the expression of a number of genes involved in commitment and differentiation of hematopoietic stem cells. Evidence shows that miRNAs play an important role in haematopoiesis; for example, myeloid and erythroid differentiation is blocked by the overexpression of miR-15a. miR-221, miR-222, and miR-24 inhibit the erythropoiesis, whereas miR-150 plays a role in B and T cell differentiation. miR-146 and miR-10a are downregulated in megakaryopoiesis. Aberrant expression of miRNAs was observed in hematological malignancies including chronic myelogenous leukemia, chronic lymphocytic leukemia, multiple myelomas, and B cell lymphomas. In this review we have focused on discussing the role of miRNA in haematopoiesis.
    Advances in Hematology 01/2013; 2013:695754.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The human dicer1 gene has been predicted to produce several mRNA variants that encode truncated Dicer1 proteins of varying lengths. One of these Dicer1 variants, Dicer1e, was recently found to be differentially expressed in breast cancer cells. Because the expression and function of the Dicer1e protein variant has not been well characterized and the underlying molecular mechanisms for the development of oral squamous cell carcinomas (OSCCs) are poorly understood, the present study sought to characterize the biological role of Dicer1e and determine its relationship, if any, to OSCC pathogenesis.
    Molecular cancer. 08/2014; 13(1):190.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The precise regulation of microRNA (miRNA) biogenesis seems to be critically important for the proper functioning of all eukaryotic organisms. Even small changes in the levels of specific miRNAs can initiate pathological processes, including carcinogenesis. Accordingly, there is a great need to develop effective methods for the regulation of miRNA biogenesis and activity. In this study, we focused on the final step of miRNA biogenesis; i.e., miRNA processing by Dicer. To test our hypothesis that RNA molecules can function not only as Dicer substrates but also as Dicer regulators, we previously identified by SELEX a pool of RNA oligomers that bind to human Dicer. We found that certain of these RNA oligomers could selectively inhibit the formation of specific miRNAs. Here, we show that these specific inhibitors can simultaneously bind both Dicer and pre-miRNAs. These bifunctional riboregulators interfere with miRNA maturation by affecting pre-miRNA structure and sequestering Dicer. Based on these observations, we designed a set of short oligomers (12 nucleotides long) that were capable of influencing pre-miRNA processing in vitro, both in reactions involving recombinant human Dicer and in cytosolic extracts. We propose that the same strategy may be used to develop effective and selective regulators to control the production of any miRNA. Overall, our findings indicate that the interactions between pre-miRNAs and other RNAs may form very complex regulatory networks that modulate miRNA biogenesis and consequently gene expression.
    PLoS ONE 01/2013; 8(10):e77703. · 3.73 Impact Factor