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Dissertation/Thesis Abstract

Structural Basis for RNA Processing by Human Dicer
by Taylor, David W., Jr., Ph.D., Yale University, 2013, 125; 3578460
Abstract (Summary)

Dicer plays a central role in RNA interference pathways by cleaving double-stranded RNAs (dsRNAs) to produce small regulatory RNAs. Human Dicer can process long double-stranded and hairpin precursor RNAs to yield short interfering RNAs (siRNAs) or microRNAs (miRNAs), respectively. In humans, Argonaute2 (AGO2) assembles with the guide RNA-generating enzyme Dicer and either the RNA-binding protein TRBP or PACT to form a RISC-loading complex (RLC), which is necessary for efficient transfer of nascent siRNAs from Dicer to AGO2. Here, I have used electron microscopy and single particle analysis of human Dicer-RNA complexes and the RLC to gain insight into the structural basis for human Dicer's substrate preference and RISC-loading. My studies show that Dicer traps pre-siRNAs in a non-productive conformation, while interactions of Dicer with pre-miRNAs and dsRNA binding proteins induce structural changes in the enzyme that enable productive substrate recognition in the central catalytic channel. The RLC Dicer's N-terminal DExH/D domain, located in a short base branch, interacts with TRBP, whereas its C-terminal catalytic domains in the main body are proximal to AGO2. A model generated by docking the available atomic structures of Dicer and Argonaute homologs into the RLC reconstruction suggests a mechanism for siRNA transfer from Dicer to AGO2.

Indexing (document details)
Advisor: Wang, Hong-Wei
School: Yale University
School Location: United States -- Connecticut
Source: DAI-B 75/05(E), Dissertation Abstracts International
Subjects: Molecular biology, Biochemistry, Biophysics
Keywords: Argonaute, Dicer, RISC-loading complex, RNA-interference, miRNAs, siRNAs
Publication Number: 3578460
ISBN: 978-1-303-71584-6
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