Sequence determinant of small RNA production by DICER

Lee, Young-Yoon; Kim, Haedong; Kim, V. Narry

doi:10.1038/s41586-023-05722-4

Cited by 33 publications

(33 citation statements)

References 56 publications

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“…Exosomes are characterized by their natural capacity to deliver miRNAs and siRNAs, which bind to mRNAs in target cells, resulting in the degradation of mRNA or inhibition of protein response processes. This leads to the silencing of target genes through a process known as RNA interference [78]. Based on this process, researchers have shifted their focus to small RNA-based therapies.…”

Section: Loading Strategies For Nucleic Acid Drugsmentioning

confidence: 99%

Current Strategies for Exosome Cargo Loading and Targeting Delivery

Zeng

Guo

Ren

et al. 2023

Cells

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Extracellular vesicles (EVs) such as ectosomes and exosomes have gained attention as promising natural carriers for drug delivery. Exosomes, which range from 30 to 100 nm in diameter, possess a lipid bilayer and are secreted by various cells. Due to their high biocompatibility, stability, and low immunogenicity, exosomes are favored as cargo carriers. The lipid bilayer membrane of exosomes also offers protection against cargo degradation, making them a desirable candidate for drug delivery. However, loading cargo into exosomes remains to be a challenge. Despite various strategies such as incubation, electroporation, sonication, extrusion, freeze–thaw cycling, and transfection that have been developed to facilitate cargo loading, inadequate efficiency still persists. This review offers an overview of current cargo delivery strategies using exosomes and summarizes recent approaches for loading small-molecule, nucleic acid, and protein drugs into exosomes. With insights from these studies, we provide ideas for more efficient and effective delivery of drug molecules by using exosomes.

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Section: Loading Strategies For Nucleic Acid Drugsmentioning

confidence: 99%

Current Strategies for Exosome Cargo Loading and Targeting Delivery

Zeng

Guo

Ren

et al. 2023

Cells

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“…A recent study proposed that the dsRBD of human Dicer recognizes the GYM motif (G guanine; Y, paired C/U; M, mismatched nucleotide) and stabilizes the interaction between the RNA and Dicer for a more efficient dicing reaction (Lee et al , 2023b). This molecular interaction could explain the evolutionary conservation of the GYM motif in a subset of miRNAs (Lee et al , 2023a).…”

Section: Dicer Function At the Molecular Levelmentioning

confidence: 99%

Dicer structure and function: conserved and evolving features

et al. 2023

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RNase III Dicer produces small RNAs guiding sequence‐specific regulations, with important biological roles in eukaryotes. Major Dicer‐dependent mechanisms are RNA interference (RNAi) and microRNA (miRNA) pathways, which employ distinct types of small RNAs. Small interfering RNAs (siRNAs) for RNAi are produced by Dicer from long double‐stranded RNA (dsRNA) as a pool of different small RNAs. In contrast, miRNAs have specific sequences because they are precisely cleaved out from small hairpin precursors. Some Dicer homologs efficiently generate both, siRNAs and miRNAs, while others are adapted for biogenesis of one small RNA type. Here, we review the wealth of recent structural analyses of animal and plant Dicers, which have revealed how different domains and their adaptations contribute to substrate recognition and cleavage in different organisms and pathways. These data imply that siRNA generation was Dicer's ancestral role and that miRNA biogenesis relies on derived features. While the key element of functional divergence is a RIG‐I‐like helicase domain, Dicer‐mediated small RNA biogenesis also documents the impressive functional versatility of the dsRNA‐binding domain.

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“…The sequence identity two nucleotides upstream and downstream of the cleavage site (5'-NN^NN-3') has also been found to modulate Dicer cleavage [37,38]. In addition, a paired guanine (G) followed by a pyrimidine (Y) and a mismatched cytosine or adenine (M) (GYM motif) near the cleavage site promotes Dicer processing at a specific position [39]. Thus, several structural features of pre-miRNA regulate miRNA maturation pathway by modulating the cleavage activity of Dicer.…”

Section: Introductionmentioning

confidence: 99%

Substrate promiscuity of Dicer toward precursors of the let-7 family and their 3'-end modifications

Dadhwal

Samy

Bouvette

et al. 2023

Preprint

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The human let-7 miRNA family consists of thirteen members that play critical roles in many biological processes, including development timing and tumor suppression, and their levels are disrupted in several diseases. Dicer is the endoribonuclease responsible for processing the precursor miRNA (pre-miRNA) to yield the mature miRNA, and thereby plays a crucial role in controlling the cellular levels of let-7 miRNAs. It is well established that the sequence and structural features of pre-miRNA hairpins such as the 5'-phosphate, the apical loop, and the 2-nt 3'-overhang are important for the processing activity of Dicer. Exceptionally, nine precursors of the let-7 family (pre-let-7) contain a 1-nt 3'-overhang and get mono-uridylated in vivo, presumably to allow efficient processing by Dicer. Pre-let-7 are also oligo-uridylated in vivo to promote their degradation and likely prevent their efficient processing by Dicer. In this study, we systematically investigated the impact of sequence and structural features of all human let-7 pre-miRNAs, including their 3'-end modifications, on Dicer binding and processing. Through the combination of SHAPE structural probing, in vitro binding and kinetic studies using purified human Dicer, we show that despite structural discrepancies among pre-let-7 RNAs, Dicer exhibits remarkable promiscuity in binding and cleaving these substrates. Moreover, the 1- or 2-nt 3'-overhang, 3'mono-uridylation and 3'-oligo-uridylation of pre-let-7 substrates appear to have little effect on Dicer binding and cleavage rate. Thus, this study extends current knowledge regarding the broad specificity of Dicer and provides novel insight regarding the effect of 3'-modifications on binding and cleavage by Dicer.

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Sequence determinant of small RNA production by DICER

Cited by 33 publications

References 56 publications

Current Strategies for Exosome Cargo Loading and Targeting Delivery

Current Strategies for Exosome Cargo Loading and Targeting Delivery

Dicer structure and function: conserved and evolving features

Substrate promiscuity of Dicer toward precursors of the let-7 family and their 3'-end modifications

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