Abstract
Short interfering RNAs (siRNAs) are processed from long double-stranded RNA (dsRNA), and a guide strand is selected and incorporated into the RNA-induced silencing complex (RISC). Within RISC, a member of the Argonaute protein family directly binds the guide strand and the siRNA guides RISC to fully complementary sites on-target RNAs, which are then sequence-specifically cleaved by the Argonaute protein—a process commonly referred to as RNA interference (RNAi). In animals, endogenous microRNAs (miRNAs) function similarly but do not lead to direct cleavage of the target RNA but to translational inhibition followed by exonucleolytic decay. This is due to only partial complementarity between the miRNA and the target RNA. SiRNAs, however, can function as miRNAs, and partial complementarity can lead to miRNA-like off-target effects in RNAi applications. Since siRNAs are widely used not only for screening but also for therapeutics as well as crop protection purposes, such miRNA-like off-target effects need to be minimized. Strategies such as RNA modifications or pooling of siRNAs have been developed and are used to reduce off-target effects.
Highlights
Double-stranded RNA as trigger for RNA interference (RNAi) has been discovered decades ago in plants and nematodes (Baulcombe, 1996; Fire et al, 1998)
In addition to the therapeutic use in mammals, RNAi is being explored as crop protection agent (Zhang et al, 2017). Double-stranded RNA (dsRNA) directed against pests such as fungi, nematodes, or insects is sprayed short interfering RNAs (siRNAs) Off-Target Effects onto the leaves of plants and upon uptake selectively affects growth of distinct target species
In plants as well as some animal species, which tolerate long dsRNA, the RNAi signal can be amplified by RNA-dependent RNA polymerases (RdRPs) (Maida et al, 2011). These enzymes use a siRNA strand bound to its target RNA as primer and synthesize the complementary strand to the target RNA resulting in a long dsRNA, which again enters Dicer processing and a second wave of siRNAs against a specific target is generated
Summary
Double-stranded RNA (dsRNA) as trigger for RNA interference (RNAi) has been discovered decades ago in plants and nematodes (Baulcombe, 1996; Fire et al, 1998). This RNA is further processed to short interfering RNAs (siRNAs), which serve as guides for the RNA-induced silencing complex (RISC) that binds and sequence- cleaves complementary target RNAs (Zamore and Haley, 2005). DsRNA directed against pests such as fungi, nematodes, or insects is sprayed siRNA Off-Target Effects onto the leaves of plants and upon uptake selectively affects growth of distinct target species.
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