Portal de Periódicos da CAPES

siRNA and miRNA: an insight into RISCs

2005; Elsevier BV; Volume: 30; Issue: 2 Linguagem: Inglês

10.1016/j.tibs.2004.12.007

1362-4326

Guiliang Tang,

interferon and immune responses

Two classes of short RNA molecule, small interfering RNA (siRNA) and microRNA (miRNA), have been identified as sequence-specific posttranscriptional regulators of gene expression. siRNA and miRNA are incorporated into related RNA-induced silencing complexes (RISCs), termed siRISC and miRISC, respectively. The current model argues that siRISC and miRISC are functionally interchangeable and target specific mRNAs for cleavage or translational repression, depending on the extent of sequence complementarity between the small RNA and its target. Emerging evidence indicates, however, that siRISC and miRISC are distinct complexes that regulate mRNA stability and translation. The assembly of RISCs can be traced from the biogenesis of the small RNA molecules and the recruitment of these RNAs by the RISC loading complex (RLC) to the transition of the RLC into the active RISC. Target recognition by the RISC can then take place through different interacting modes. Two classes of short RNA molecule, small interfering RNA (siRNA) and microRNA (miRNA), have been identified as sequence-specific posttranscriptional regulators of gene expression. siRNA and miRNA are incorporated into related RNA-induced silencing complexes (RISCs), termed siRISC and miRISC, respectively. The current model argues that siRISC and miRISC are functionally interchangeable and target specific mRNAs for cleavage or translational repression, depending on the extent of sequence complementarity between the small RNA and its target. Emerging evidence indicates, however, that siRISC and miRISC are distinct complexes that regulate mRNA stability and translation. The assembly of RISCs can be traced from the biogenesis of the small RNA molecules and the recruitment of these RNAs by the RISC loading complex (RLC) to the transition of the RLC into the active RISC. Target recognition by the RISC can then take place through different interacting modes. A large protein family that constitutes key components of RISCs. AGO proteins are characterized by two unique domains, PAZ and PIWI, whose functions are not fully understood. Current evidence suggests that the PAZ domain binds the 3′-end two-nucleotide overhangs of the siRNA duplex, whereas the PIWI domain of some AGO proteins confers slicer activity. PAZ and PIWI domains are both essential to guide the interaction between the siRNA and the target mRNA for cleavage or translational repression. Distinct AGO members have distinct functions. For example, human AGO2 programs RISCs to cleave the mRNA target, whereas AGO1 and AGO3 do not. A cleaving or cleavage-competent RISC that contains an endonuclease or slicer activity that binds a target for cleavage. The endonuclease or slicer identity has not been clearly identified in most organisms. Much evidence suggests that some types of AGO protein or their tightly associated identities are candidates for such an endonuclease. A cleaving RISC can direct a specific target mRNA for cleavage or translational repression, depending on the base-pairing conditions between the small RNA and the mRNA target. The smallest RNA–protein complex that can direct a target mRNA for cleavage or translational repression. The RISCs of <200 kDa identified in humans and Drosophila might represent the core RISC. AGO proteins are associated with the core RISC. A protein, first identified in C. elegans, that has most homology to the helicase domain of DCR. There are two DRHs: DRH-1 and DRH-2. Both interact with the dsRNA-binding protein RDE-4 and are required for RNAi in C. elegans. Neither seems to be required for miRNA production. A multidomain enzyme of the RNase III family that was first identified in Drosophila. DCR cleaves dsRNA or stem-loop structured RNA precursors into small RNAs (∼21–25 nucleotides), termed siRNAs and miRNAs. DCR is widely conserved in diverse organisms. A nuclear RNase III enzyme, discovered first in humans and subsequently in Drosophila and C. elegans that is implicated in initiation of the miRNA pathway. A nuclear transmembrane protein that transports precursor miRNA from the nucleus to the cytosol. The largest RNA–protein complex (80S) with RISC activity that has been found in Drosophila. The holo RISC associates with all possible RISC components, RLC components and proteins from other pathways. The existence of the holo RISC indicates that RISC assembly is an inseparable and sequential process and that the RISC-centered RNAi and miRNA pathways closely interact with many other pathways, possibly to control the growth and development of an organism. A nuclear complex composed of Drosha and Pasha that functions in miRNA biogenesis from the primary miRNA to the precursor miRNA. A type of non-coding small RNA (∼21–23 nucleotides) produced by DCR from a stem-loop structured RNA precursor. miRNAs are widely expressed in animal and plant cells as RNA–protein complexes, termed miRISCs, and have been implicated in the control of development because they target specific gene transcripts for destruction or translational suppression. A RISC that lacks endonuclease activity and thus cannot target mRNA for cleavage but only for translational repression. A partner of Drosha in the nucleus. Pasha is a dsRNA-binding protein similar to RDE-4 and R2D2. Pasha interacts with Drosha to initiate miRNA biogenesis. In humans, Pasha is also known as DGCR8. A dsRNA-binding protein that has two dsRNA-binding domains and interacts with DCR2 for stability in Drosophila. R2D2 is thought to function as both a bridge and a sensor for functional RISC assembly. An AGO protein discovered in C. elegans. Without RDE-1, RNAi ability is aborted (RNAi defective). RDE-1 has been proposed to interact with DCR-1, RDE-4 and DRH-1, probably for the formation of a stable protein complex that produces robust siRNAs and directs functional RISC assembly. RDE-1 does not seem to be required for miRNA production and function. A dsRNA-binding protein discovered in C. elegans. Without RDE-4, RNAi ability is aborted (RNAi defective). RDE-4 is the homolog of R2D2. Unlike R2D2, RDE-4 has been proposed to function as the factor that presents dsRNA to DCR-1 for dicing, rather than the factor that hands siRNA to the RISC. RDE-4 does not seem to be required for miRNA production and function. A complex that initiates formation of a RISC. The RLC sets a small RNA duplex in proper orientation for subsequent RISC assembly. Currently, siRISC-loading complexes (siRLCs) have been studied most extensively in Drosophila. It has been suggested that Drosophila siRLCs contain a DCR2–R2D2 heterodimer and the siRNA duplex; the R2D2 moiety is the asymmetric sensor that sets the siRNA orientation for RISC assembly. miRISC-loading complexes (miRLCs) have not been investigated because the biogenesis of a miRNA is more complex and an in vitro system for studying miRLCs has not been established. A complex that directs chromatin remodeling. The RITS complex also contains DCR-generated siRNA and AGO protein, and functions in heterochromatic silencing by binding to heterochromatic loci. An RNA–protein complex that targets its perfectly or partially complementary mRNA for cleavage or translational repression. siRNA programs a siRISC and miRNA programs a miRISC. RISCs (both siRISC and miRISC) can be divided into two types: cleaving and non-cleaving. Current evidence suggests that the type of AGO protein, an essential RISC component, determines whether a RISC is cleaving or non-cleaving. Another term for the endonuclease located on a cleaving RISC. A type of small RNA (∼21–25 nucleotides) produced by DCR, a double-stranded RNA-specific enzyme of the RNAse III family. The siRNA is the key component of siRISCs and triggers the silencing of its complementary mRNA. Unit of sedimentation rate for measuring a particle size in a centrifuge.