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TRBP recruits the Dicer complex to Ago2 for microRNA processing and gene silencing

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  • Thimmaiah P. Chendrimada

    (The Wistar Institute)

  • Richard I. Gregory

    (The Wistar Institute)

  • Easwari Kumaraswamy

    (The Wistar Institute
    The Children's Hospital of Philadelphia)

  • Jessica Norman

    (The Wistar Institute)

  • Neil Cooch

    (The Wistar Institute)

  • Kazuko Nishikura

    (The Wistar Institute)

  • Ramin Shiekhattar

    (The Wistar Institute)

Abstract

MicroRNAs (miRNAs) are generated by a two-step processing pathway to yield RNA molecules of approximately 22 nucleotides that negatively regulate target gene expression at the post-transcriptional level1. Primary miRNAs are processed to precursor miRNAs (pre-miRNAs) by the Microprocessor complex2,3,4. These pre-miRNAs are cleaved by the RNase III Dicer5,6,7,8 to generate mature miRNAs that direct the RNA-induced silencing complex (RISC) to messenger RNAs with complementary sequence9. Here we show that TRBP (the human immunodeficiency virus transactivating response RNA-binding protein10), which contains three double-stranded, RNA-binding domains, is an integral component of a Dicer-containing complex. Biochemical analysis of TRBP-containing complexes revealed the association of Dicer–TRBP with Argonaute 2 (Ago2)11,12, the catalytic engine of RISC. The physical association of Dicer–TRBP and Ago2 was confirmed after the isolation of the ternary complex using Flag-tagged Ago2 cell lines. In vitro reconstitution assays demonstrated that TRBP is required for the recruitment of Ago2 to the small interfering RNA (siRNA) bound by Dicer. Knockdown of TRBP results in destabilization of Dicer and a consequent loss of miRNA biogenesis. Finally, depletion of the Dicer–TRBP complex via exogenously introduced siRNAs diminished RISC-mediated reporter gene silencing. These results support a role of the Dicer–TRBP complex not only in miRNA processing but also as a platform for RISC assembly.

Suggested Citation

  • Thimmaiah P. Chendrimada & Richard I. Gregory & Easwari Kumaraswamy & Jessica Norman & Neil Cooch & Kazuko Nishikura & Ramin Shiekhattar, 2005. "TRBP recruits the Dicer complex to Ago2 for microRNA processing and gene silencing," Nature, Nature, vol. 436(7051), pages 740-744, August.
  • Handle: RePEc:nat:nature:v:436:y:2005:i:7051:d:10.1038_nature03868
    DOI: 10.1038/nature03868
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    Cited by:

    1. Alfons Navarro & Carmen Muñoz & Anna Gaya & Marina Díaz-Beyá & Bernat Gel & Rut Tejero & Tania Díaz & Antonio Martinez & Mariano Monzó, 2013. "MiR-SNPs as Markers of Toxicity and Clinical Outcome in Hodgkin Lymphoma Patients," PLOS ONE, Public Library of Science, vol. 8(5), pages 1-10, May.
    2. Xue Fang & Zhihua Yin & Xuelian Li & Lingzi Xia & Baosen Zhou, 2016. "Polymorphisms in GEMIN4 and AGO1 Genes Are Associated with the Risk of Lung Cancer: A Case-Control Study in Chinese Female Non-Smokers," IJERPH, MDPI, vol. 13(10), pages 1-13, September.
    3. Le Thi Truc Linh, 2018. "The Microrna 29 family and its regulation," HO CHI MINH CITY OPEN UNIVERSITY JOURNAL OF SCIENCE - ENGINEERING AND TECHNOLOGY, HO CHI MINH CITY OPEN UNIVERSITY JOURNAL OF SCIENCE, HO CHI MINH CITY OPEN UNIVERSITY, vol. 8(1), pages 18-27.
    4. Shuangmei Tian & Ziyu Zhao & Beibei Ren & Degeng Wang, 2024. "Non-Linear Relationship between MiRNA Regulatory Activity and Binding Site Counts on Target mRNAs," Data, MDPI, vol. 9(10), pages 1-13, September.
    5. Justine M Pompey & Bardees Foda & Upinder Singh, 2015. "A Single RNaseIII Domain Protein from Entamoeba histolytica Has dsRNA Cleavage Activity and Can Help Mediate RNAi Gene Silencing in a Heterologous System," PLOS ONE, Public Library of Science, vol. 10(7), pages 1-21, July.

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