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Dicer dependent tRNA derived small RNAs promote nascent RNA silencing

In mammalian cells, small non-coding RNAs (sncRNAs) negatively regulate gene expression in a pathway known as RNA interference (RNAi). RNAi can be categorized into post-transcriptional gene silencing (PTGS), which involves the cleavage of target messenger RNA (mRNA) or inhibition of translation in t...

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Autores principales: Di Fazio, Arianna, Schlackow, Margarita, Pong, Sheng Kai, Alagia, Adele, Gullerova, Monika
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8860591/
https://www.ncbi.nlm.nih.gov/pubmed/35048990
http://dx.doi.org/10.1093/nar/gkac022
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author Di Fazio, Arianna
Schlackow, Margarita
Pong, Sheng Kai
Alagia, Adele
Gullerova, Monika
author_facet Di Fazio, Arianna
Schlackow, Margarita
Pong, Sheng Kai
Alagia, Adele
Gullerova, Monika
author_sort Di Fazio, Arianna
collection PubMed
description In mammalian cells, small non-coding RNAs (sncRNAs) negatively regulate gene expression in a pathway known as RNA interference (RNAi). RNAi can be categorized into post-transcriptional gene silencing (PTGS), which involves the cleavage of target messenger RNA (mRNA) or inhibition of translation in the cytoplasm, and transcriptional gene silencing (TGS), which is mediated by the establishment of repressive epigenetic marks at target loci. Transfer RNAs (tRNAs), which are essential for translation, can be processed into small ncRNAs, termed tRNA-derived small RNAs (tsRNAs). The biogenesis of tsRNAs and their role in gene expression regulation has not yet been fully understood. Here, we show that Dicer dependent tsRNAs promote gene silencing through a mechanism distinct from PTGS and TGS. tsRNAs can lead to downregulation of target genes by targeting introns via nascent RNA silencing (NRS) in nuclei. Furthermore, we show that Ago2 slicer activity is required for this mechanism. Synthetic tsRNAs can significantly reduce expression of a target gene at both RNA and protein levels. Target genes regulated by NRS are associated with various diseases, which further underpins its biological significance. Finally, we show that NRS is evolutionarily conserved and has the potential to be explored as a novel synthetic sRNA based therapeutic.
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spelling pubmed-88605912022-02-22 Dicer dependent tRNA derived small RNAs promote nascent RNA silencing Di Fazio, Arianna Schlackow, Margarita Pong, Sheng Kai Alagia, Adele Gullerova, Monika Nucleic Acids Res RNA and RNA-protein complexes In mammalian cells, small non-coding RNAs (sncRNAs) negatively regulate gene expression in a pathway known as RNA interference (RNAi). RNAi can be categorized into post-transcriptional gene silencing (PTGS), which involves the cleavage of target messenger RNA (mRNA) or inhibition of translation in the cytoplasm, and transcriptional gene silencing (TGS), which is mediated by the establishment of repressive epigenetic marks at target loci. Transfer RNAs (tRNAs), which are essential for translation, can be processed into small ncRNAs, termed tRNA-derived small RNAs (tsRNAs). The biogenesis of tsRNAs and their role in gene expression regulation has not yet been fully understood. Here, we show that Dicer dependent tsRNAs promote gene silencing through a mechanism distinct from PTGS and TGS. tsRNAs can lead to downregulation of target genes by targeting introns via nascent RNA silencing (NRS) in nuclei. Furthermore, we show that Ago2 slicer activity is required for this mechanism. Synthetic tsRNAs can significantly reduce expression of a target gene at both RNA and protein levels. Target genes regulated by NRS are associated with various diseases, which further underpins its biological significance. Finally, we show that NRS is evolutionarily conserved and has the potential to be explored as a novel synthetic sRNA based therapeutic. Oxford University Press 2022-01-20 /pmc/articles/PMC8860591/ /pubmed/35048990 http://dx.doi.org/10.1093/nar/gkac022 Text en © The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle RNA and RNA-protein complexes
Di Fazio, Arianna
Schlackow, Margarita
Pong, Sheng Kai
Alagia, Adele
Gullerova, Monika
Dicer dependent tRNA derived small RNAs promote nascent RNA silencing
title Dicer dependent tRNA derived small RNAs promote nascent RNA silencing
title_full Dicer dependent tRNA derived small RNAs promote nascent RNA silencing
title_fullStr Dicer dependent tRNA derived small RNAs promote nascent RNA silencing
title_full_unstemmed Dicer dependent tRNA derived small RNAs promote nascent RNA silencing
title_short Dicer dependent tRNA derived small RNAs promote nascent RNA silencing
title_sort dicer dependent trna derived small rnas promote nascent rna silencing
topic RNA and RNA-protein complexes
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8860591/
https://www.ncbi.nlm.nih.gov/pubmed/35048990
http://dx.doi.org/10.1093/nar/gkac022
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