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Potent degradation of neuronal miRNAs induced by highly complementary targets


de la Mata, M; Gaidatzis, D; Vitanescu, M; Stadler, M B; Wentzel, C; Scheiffele, P; Filipowicz, W; Grosshans, H (2015). Potent degradation of neuronal miRNAs induced by highly complementary targets. EMBO Reports, 16(4):500-511.

Abstract

MicroRNAs (miRNAs) regulate target mRNAs by silencing them. Reciprocally, however, target mRNAs can also modulate miRNA stability. Here, we uncover a remarkable efficacy of target RNA‐directed miRNA degradation (TDMD) in rodent primary neurons. Coincident with degradation, and while still bound to Argonaute, targeted miRNAs are 3′ terminally tailed and trimmed. Absolute quantification of both miRNAs and their decay‐inducing targets suggests that neuronal TDMD is multiple turnover and does not involve co‐degradation of the target but rather competes with miRNA‐mediated decay of the target. Moreover, mRNA silencing, but not TDMD, relies on cooperativity among multiple target sites to reach high efficacy. This knowledge can be harnessed for effective depletion of abundant miRNAs. Our findings bring insight into a potent miRNA degradation pathway in primary neurons, whose TDMD activity greatly surpasses that of non‐neuronal cells and established cell lines. Thus, TDMD may be particularly relevant for miRNA regulation in the nervous system.

Abstract

MicroRNAs (miRNAs) regulate target mRNAs by silencing them. Reciprocally, however, target mRNAs can also modulate miRNA stability. Here, we uncover a remarkable efficacy of target RNA‐directed miRNA degradation (TDMD) in rodent primary neurons. Coincident with degradation, and while still bound to Argonaute, targeted miRNAs are 3′ terminally tailed and trimmed. Absolute quantification of both miRNAs and their decay‐inducing targets suggests that neuronal TDMD is multiple turnover and does not involve co‐degradation of the target but rather competes with miRNA‐mediated decay of the target. Moreover, mRNA silencing, but not TDMD, relies on cooperativity among multiple target sites to reach high efficacy. This knowledge can be harnessed for effective depletion of abundant miRNAs. Our findings bring insight into a potent miRNA degradation pathway in primary neurons, whose TDMD activity greatly surpasses that of non‐neuronal cells and established cell lines. Thus, TDMD may be particularly relevant for miRNA regulation in the nervous system.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:07 Faculty of Science > Institute of Molecular Life Sciences
Dewey Decimal Classification:570 Life sciences; biology
Language:English
Date:2015
Deposited On:16 Dec 2015 16:36
Last Modified:18 Apr 2018 11:46
Publisher:Nature Publishing Group
ISSN:1469-221X
Funders:European Union Seventh Framework Programme FP7/2007‐2013 241985, Swiss National Science Foundation, Novartis Research Foundation, Human Frontier Science Program LT000087/2009‐L, Peter und Traudl Engelhorn‐Stiftung
OA Status:Closed
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.15252/embr.201540078
Project Information:
  • : FunderFP7
  • : Grant ID241985
  • : Project TitleMIRTURN - Mechanisms of microRNA biogenesis and turnover
  • : FunderFP7
  • : Grant ID
  • : Project TitleEuropean Union Seventh Framework Programme FP7/2007‐2013 241985
  • : FunderSNSF
  • : Grant ID
  • : Project TitleSwiss National Science Foundation
  • : Funder
  • : Grant ID
  • : Project TitleNovartis Research Foundation
  • : Funder
  • : Grant ID
  • : Project TitleHuman Frontier Science Program LT000087/2009‐L
  • : Funder
  • : Grant ID
  • : Project TitlePeter und Traudl Engelhorn‐Stiftung

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