Structural Basis for Target-Directed MicroRNA Degradation

Sheu‐Gruttadauria, Jessica; Pawlica, Paulina; Klum, Shannon; Wang, Sonia; Yario, Therese A.; Oakdale, Nicole T. Schirle; Steitz, Joan A.; MacRae, Ian J.

doi:10.1016/j.molcel.2019.06.019

Cited by 202 publications

(256 citation statements)

References 74 publications

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“…The formation of the RISC stabilizes both miRNAs and Ago proteins. Several mechanisms of miRNA destabilization including Tudor-SN-mediated endonucleolytic decay and target-directed miRNA destabilization, which frequently involves 3 end tailing and trimming and yields miRNA isoforms (isomiRs), have been described [23,24].…”

Section: Quantitative Features Of Mirna Biogenesis and Functionmentioning

confidence: 99%

Systems and Synthetic microRNA Biology: From Biogenesis to Disease Pathogenesis

Matsuyama

Suzuki

2019

IJMS

194

141

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MicroRNAs (miRNAs) are approximately 22-nucleotide-long, small non-coding RNAs that post-transcriptionally regulate gene expression. The biogenesis of miRNAs involves multiple steps, including the transcription of primary miRNAs (pri-miRNAs), nuclear Drosha-mediated processing, cytoplasmic Dicer-mediated processing, and loading onto Argonaute (Ago) proteins. Further, miRNAs control diverse biological and pathological processes via the silencing of target mRNAs. This review summarizes recent findings regarding the quantitative aspects of miRNA homeostasis, including Drosha-mediated pri-miRNA processing, Ago-mediated asymmetric miRNA strand selection, and modifications of miRNA pathway components, as well as the roles of RNA modifications (epitranscriptomics), epigenetics, transcription factor circuits, and super-enhancers in miRNA regulation. These recent advances have facilitated a system-level understanding of miRNA networks, as well as the improvement of RNAi performance for both gene-specific targeting and genome-wide screening. The comprehensive understanding and modeling of miRNA biogenesis and function have been applied to the design of synthetic gene circuits. In addition, the relationships between miRNA genes and super-enhancers provide the molecular basis for the highly biased cell type-specific expression patterns of miRNAs and the evolution of miRNA–target connections, while highlighting the importance of alterations of super-enhancer-associated miRNAs in a variety of human diseases.

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Section: Quantitative Features Of Mirna Biogenesis and Functionmentioning

confidence: 99%

Systems and Synthetic microRNA Biology: From Biogenesis to Disease Pathogenesis

Matsuyama

Suzuki

2019

IJMS

194

141

View full text Add to dashboard Cite

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“…These RNAs vary not only in class and origin, but also seem to have flexible requirements for base-pairing with miRNAs to induce TDMD. In addition, HSUR1 mutagenesis further expanded the range of possible miRNA-TDMD target interactions (Table 2; Sheu-Gruttadauria and Pawlica et al 2019).…”

mentioning

confidence: 99%

“…Moreover, the molecular mechanism of TDMD remained elusive for nearly 10 years. Our recent paper provides critical structural insights into how TDMD targets trap Ago2 in an extended conformation with the miRNA 3 0 end displayed for cellular tailing (nontemplated nucleotide additions) and trimming while remaining bound to Ago proteins (Sheu-Gruttadauria and Pawlica et al 2019).…”

mentioning

confidence: 99%

How Complementary Targets Expose the microRNA 3′ End for Tailing and Trimming during Target-Directed microRNA Degradation

Pawlica

Sheu‐Gruttadauria

MacRae

et al. 2019

Cold Spring Harb Symp Quant Biol

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microRNAs (miRNAs) are crucial for posttranscriptional regulation of messenger RNAs. "Classical" miRNA targets predominantly interact with the miRNA seed sequence located near the miRNA 5 0 end. Interestingly, certain transcripts that exhibit extensive complementarity to the miRNAs 3 0 region, instead of being subjected to regulation, induce miRNA decay in a process termed target-directed miRNA degradation (TDMD). Here, we review recent advances in understanding the molecular mechanisms of TDMD. Specifically, we discuss how extensive miRNA complementarity to TDMD-inducing targets results in displacement of the miRNA 3 0 end from its protective pocket in the Argonaute protein. Unprotected miRNA 3 0 ends are then available for enzymatic attack by still-unidentified cellular enzymes. Identification of these cellular enzymes and discovery of additional TDMD-inducing transcripts are subjects for future research.

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“…Finally, some studies suggest that supplementary binding to the target mRNA outside the seed region can alter the orientation of miRNA in the Ago protein [57], leading to tailing (addition of A/U non-template nucleotides), trimming, or shortening of the 3 -end, which results in miRNA degradation instead of mRNA silencing. This phenomenon, target RNA-directed microRNA degradation, is observed in Drosophila [58], zebra fish [59], mouse brain [59,60], and in cells infected by human cytomegalovirus [61][62][63].…”

Section: Tbi Causes Downregulation Of Mir-124-3p In the Perilesional mentioning

confidence: 99%

Chronic Regulation of miR-124-3p in the Perilesional Cortex after Experimental and Human TBI

Vuokila

Aronica

Korotkov

et al. 2020

IJMS

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Traumatic brain injury (TBI) dysregulates microRNAs, which are the master regulators of gene expression. Here we investigated the changes in a brain-enriched miR-124-3p, which is known to associate with major post-injury pathologies, such as neuroinflammation. RT-qPCR of the rat tissue sampled at 7 d and 3 months in the perilesional cortex adjacent to the necrotic lesion core (aPeCx) revealed downregulation of miR-124-3p at 7 d (fold-change (FC) 0.13, p < 0.05 compared with control) and 3 months (FC 0.40, p < 0.05) post-TBI. In situ hybridization confirmed the downregulation of miR-124-3p at 7 d and 3 months post-TBI in the aPeCx (both p < 0.01). RT-qPCR confirmed the upregulation of the miR-124-3p target Stat3 in the aPeCx at 7 d post-TBI (7-fold, p < 0.05). mRNA-Seq revealed 312 downregulated and 311 upregulated miR-124 targets (p < 0.05). To investigate whether experimental findings translated to humans, we performed in situ hybridization of miR-124-3p in temporal lobe autopsy samples of TBI patients. Our data revealed downregulation of miR-124-3p in individual neurons of cortical layer III. These findings indicate a persistent downregulation of miR-124-3p in the perilesional cortex that might contribute to post-injury neurodegeneration and inflammation.

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Structural Basis for Target-Directed MicroRNA Degradation

Cited by 202 publications

References 74 publications

Systems and Synthetic microRNA Biology: From Biogenesis to Disease Pathogenesis

Systems and Synthetic microRNA Biology: From Biogenesis to Disease Pathogenesis

How Complementary Targets Expose the microRNA 3′ End for Tailing and Trimming during Target-Directed microRNA Degradation

Chronic Regulation of miR-124-3p in the Perilesional Cortex after Experimental and Human TBI

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