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Biogenesis and function of endogenous and exogenous siRNAs

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Abstract RNA interference (RNAi) is a sequence‐specific gene silencing, or ‘knockdown’, mechanism facilitated by short duplex strands of RNA with sequence complementarity to target mRNAs. RNAi has many different forms, including posttranscriptional gene silencing (PTGS), and transcriptional gene silencing (TGS). Here, we review the biogenesis and function of an endogenous set of small RNA gene regulators, called microRNAs, as well as the mechanism of exogenously delivered small interfering RNAs. The potential applications of RNAi‐based therapeutics are also highlighted. Copyright © 2010 John Wiley & Sons, Ltd. This article is categorized under: Regulatory RNAs/RNAi/Riboswitches > Biogenesis of Effector Small RNAs Regulatory RNAs/RNAi/Riboswitches > RNAi: Mechanisms of Action RNA in Disease and Development > RNA in Disease

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Comparison of endogenous siRNA structure and chemistry with two siRNA variants. For simplicity, the bottom strand is the designated guide strand. (A) Endogenous, Dicer‐generated siRNA is composed of RNA nucleotides (dark blue) with a 19–20 duplex region and two‐nucleotide overhangs on both of the 3 ends. The 5 ends are monophosphorylated (P) and the 3 ends contain 3 hydroxyls (OH). (B) Commonly, exogenous siRNA are synthesized with a 19–20 bp RNA nucleotide duplex region but with DNA (orange) nucleotides as the 3 two‐nucleotide overhangs. The 5 monophosphorylation and 3 OH are maintained. (C) An example of the Dicer substrate interfering RNA (dsiRNA) variant. The dsiRNA's asymmetry and modifications display favorable silencing and guide strand selection properties. The 25 nt passenger strand is perfectly complementary to the guide strand and contains paired DNA nucleotides as the last two 3 terminal nucleotides. The guide strand is 27 nt long, is composed of RNA nucleotides, and has a two‐nucleotide 3 overhang. The 5 monophosphate and 3 OH are maintained.

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Overview of the RNAi (left) and miRNA (right) pathways. MiRNA biogenesis begins in the nucleus. (1) Newly transcribed pri‐miRNAs are processed to pre‐miRNAs by the Drosha/DGCR8 heterodimer. (2) Pre‐miRNAs are exported to the cytoplasm by Exportin‐5. (3) Cytoplasmic pre‐miRNA is bound and further processed by the Dicer/TRBP heterodimer to yield the duplex miRNA. (4) Ago2 or Ago1 is recruited to form the RNA‐induced silencing complex (RISC) loading complex (RLC). (5) The guide strand is selected and the passenger strand is released, generating the miRISC. (6B) Nearly all mammalian miRNAs bind with imperfect complementarity to their target mRNAs' (red strand) 3 UTR. Other miRISC co‐factors (rck/p54, GW182, etc.) facilitate translational repression. (3) Exogenously delivered siRNA or RNAi triggers act in cytoplasm and are bound and processed by Dicer/TRBP. (4, 5) Subsequently, siRNA proceed through nearly identical processing steps as the miRNA pathway to form the siRISC. (6A) Most exogenous siRNAs are designed to bind with complete complementarity to target mRNA, triggering cleavage of the target mRNA. ShRNA (not shown) proceed through steps similar to miRNAs (2, 3, 4) but transition to the siRNA pathway (5, 6A) upon siRISC formation.

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RNA in Disease and Development > RNA in Disease
Regulatory RNAs/RNAi/Riboswitches > RNAi: Mechanisms of Action
Regulatory RNAs/RNAi/Riboswitches > Biogenesis of Effector Small RNAs

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