mRNA degradation by miRNAs and GW182 requires both CCR4:NOT deadenylase and DCP1:DCP2 decapping complexes.
By I. Behm-Ansmant, J. Rehwinkel, Tobias Doerks, Alexander Stark, Peer Bork, Elisa Izaurralde. Genes & Development, 2006
1,103 citations recorded by the source corpus.
MicroRNAs (miRNAs) silence the expression of target genes post-transcriptionally. Their function is mediated by the Argonaute proteins (AGOs), which colocalize to P-bodies with mRNA degradation enzymes. Mammalian P-bodies are also marked by the GW182 protein, which interacts with the AGOs and is required for miRNA function. We show that depletion of GW182 leads to changes in mRNA expression profiles strikingly similar to those observed in cells depleted of the essential Drosophila miRNA effector AGO1, indicating that GW182 functions in the miRNA pathway. When GW182 is bound to a reporter transcript, it silences its expression, bypassing the requirement for AGO1. Silencing by GW182 is effected by changes in protein expression and mRNA stability. Similarly, miRNAs silence gene expression by repressing protein expression and/or by promoting mRNA decay, and both mechanisms require GW182. mRNA degradation, but not translational repression, by GW182 or miRNAs is inhibited in cells depleted of CAF1, NOT1, or the decapping DCP1:DCP2 complex. We further show that the N-terminal GW repeats of GW182 interact with the PIWI domain of AGO1. Our findings indicate that GW182 links the miRNA pathway to mRNA degradation by interacting with AGO1 and promoting decay of at least a subset of miRNA targets.
Subfields: Cancer Research, Molecular Biology
View Paper: https://www.semanticscholar.org/paper/38361f5056ce627c20f6818393a2131517a2f901
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Citations in the corpus
- Argonaute proteins: key players in RNA silencing (2008, background): “GW182 also has a role in miRNA-mediated gene regulation, which might function downstream of AGO1 in flie”
- m6A-dependent regulation of messenger RNA stability (2013, positive): “In further support of this mechanism, N-YTHDF2 was fused with λ peptide (N-YTHDF2-λ ) which recognizes Box B RNA with a high affinity in a tether reporter assay 29,30 .”
- Biogenesis, Turnover, and Mode of Action of Plant MicroRNAs[OPEN] (2013, background): “GW-repeat domains are known to interact directly with the PIWI domains of AGO proteins within the RISC (Behm-Ansmant et al., 2006; El-Shami et al., 2007; Till et al., 2007).”
- Mechanisms of miRNA-mediated post-transcriptional regulation in animal cells. (2009, background): “The N-terminal GW repeats were shown to be responsible for the interaction with AGO proteins [11,17,77 ] and disruption of GW182–AGO interaction with point mutations or a peptide competing with GW182 for AGO binding also abrogated miRNAmediated repression [37 ,77 ].”
- P-Body Formation Is a Consequence, Not the Cause, of RNA-Mediated Gene Silencing (2007, methodology): “4) (17, 26, 31, 34, 59), and proteins involved in GW182-mediated decay (i.e., DCP1, DCP2, CCR4, and CAF1) localize to P bodies (4, 16, 17, 44, 49).”
- Overview of MicroRNA Biogenesis, Mechanisms of Actions, and Circulation (2018, background): “The formation of a silencing miRISC complex starts with the recruitment of the GW182 family of proteins by miRISC; GW182 provides the scaffolding needed to recruit other effector proteins (52), such as the poly(A)-deadenylase complexes PAN2-PAN3 and CCR4-NOT, following miRNA:target mRNA interaction ”
- The Functions of MicroRNAs: mRNA Decay and Translational Repression. (2015, background): “Indeed, in Drosophila S2 cells, depletion of GW182 almost completely abolisheddeadenylation and subsequentmRNAdecay, but only partially compromised silencing at the protein level [20,47,103].”
- N6-methyladenosine Modulates Messenger RNA Translation Efficiency (2015, neutral): “(Behm-Ansmant et al., 2006).”