Main constraints for RNAi induced by expressed long dsRNA in mouse cells.
Animals
Base Sequence
/ genetics
Carrier Proteins
/ metabolism
DEAD-box RNA Helicases
/ metabolism
Gene Knockout Techniques
Mice
MicroRNAs
/ metabolism
NIH 3T3 Cells
Plasmids
/ genetics
RNA Interference
/ physiology
RNA, Double-Stranded
/ genetics
RNA, Small Interfering
/ metabolism
RNA-Binding Proteins
/ metabolism
Ribonuclease III
/ metabolism
Transfection
eIF-2 Kinase
/ genetics
Journal
Life science alliance
ISSN: 2575-1077
Titre abrégé: Life Sci Alliance
Pays: United States
ID NLM: 101728869
Informations de publication
Date de publication:
02 2019
02 2019
Historique:
received:
27
12
2018
revised:
09
02
2019
accepted:
11
02
2019
entrez:
28
2
2019
pubmed:
28
2
2019
medline:
28
2
2019
Statut:
epublish
Résumé
RNAi is the sequence-specific mRNA degradation guided by siRNAs produced from long dsRNA by RNase Dicer. Proteins executing RNAi are present in mammalian cells but rather sustain the microRNA pathway. Aiming for a systematic analysis of mammalian RNAi, we report here that the main bottleneck for RNAi efficiency is the production of functional siRNAs, which integrates Dicer activity, dsRNA structure, and siRNA targeting efficiency. Unexpectedly, increased expression of Dicer cofactors TARBP2 or PACT reduces RNAi but not microRNA function. Elimination of protein kinase R, a key dsRNA sensor in the interferon response, had minimal positive effects on RNAi activity in fibroblasts. Without high Dicer activity, RNAi can still occur when the initial Dicer cleavage of the substrate yields an efficient siRNA. Efficient mammalian RNAi may use substrates with some features of microRNA precursors, merging both pathways even more than previously suggested. Although optimized endogenous Dicer substrates mimicking miRNA features could evolve for endogenous regulations, the same principles would make antiviral RNAi inefficient as viruses would adapt to avoid efficacy.
Identifiants
pubmed: 30808654
pii: 2/1/e201800289
doi: 10.26508/lsa.201800289
pmc: PMC6391682
pii:
doi:
Substances chimiques
Carrier Proteins
0
MicroRNAs
0
RNA, Double-Stranded
0
RNA, Small Interfering
0
RNA-Binding Proteins
0
Rbbp6 protein, mouse
0
trans-activation responsive RNA-binding protein
136628-24-5
eIF-2 Kinase
EC 2.7.11.1
protein kinase R, mouse
EC 2.7.11.1
Dicer1 protein, mouse
EC 3.1.26.3
Ribonuclease III
EC 3.1.26.3
DEAD-box RNA Helicases
EC 3.6.4.13
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2019 Demeter et al.
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