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Novel roles of the CCR4–NOT complex

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The CCR4–NOT complex is a multi‐subunit protein complex evolutionarily conserved across eukaryotes which regulates several aspects of gene expression. A fascinating model is emerging in which this complex acts as a regulation platform, controlling gene products ‘from birth to death’ through the coordination of different cellular machineries involved in diverse cellular functions. Recently the CCR4–NOT functions have been extended to the control of the innate immune response through the regulation of interferon signaling. Thus, a more comprehensive picture of how CCR4–NOT allows the rapid adaptation of cells to external stress, from transcription to mRNA and protein decay, is presented and discussed here. Overall, CCR4–NOT permits the efficient and rapid adaptation of cellular gene expression in response to changes in environmental conditions and stimuli. WIREs RNA 2014, 5:883–901. doi: 10.1002/wrna.1254 This article is categorized under: RNA Processing > 3' End Processing RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms
CCR4–NOT and translational repression: the case of miRISC‐induced silencing. The GW182 subunit of miRNA‐induced silencing complex (miRISC) recruits CCR4–NOT, leading to mRNA deadenylation and inhibition of translation initiation. Different mechanisms of CCR4–NOT‐dependent translational repression are illustrated. (a) The CNOT subunits interact with several translational repressors which could block the translational initiation step via an interference with the 43S Preinitiation complex (43S PIC). (b) CCR4–NOT interacts with the decapping activator DDX6 which is required for miRNA‐induced translational repression. (c) GW182‐recruited CCR4–NOT causes dissociation of PABP from silenced mRNA poly(A) tails in the absence of deadenylation. (d) CCR4–NOT degrades the poly(A) tail of miRNA target mRNAs, inducing the removal of the cap by the decapping DCP1/2 enzymes.
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Model for dual regulatory functions of CCR4–NOT in IFN/STAT1 signaling. (a) Under physiological conditions, the hCAF1 subunit of CCR4–NOT can control STAT1 function by interacting with STAT1 in the cytoplasm in the absence of IFN induction. IFN activation leads to the release of STAT1 and its phosphorylation. Phosphorylated STAT1 forms homodimers or heterodimers which move to the nucleus and induce the transcription of target genes. During this process, CNOT4 acts as a positive regulator of the STAT1 activation. Moreover CCR4–NOT participates in the extinction of IFN signal via the deadenylase module by speeding up the degradation of several STAT1‐regulated mRNAs. (b) In cells with a knockdown of hCAF1 expression (hCAF1kd), hCAF1 depletion prevents the sequestering of STAT1 to the cytoplasm, permitting a fraction of unphosphorylated STAT1 to migrate into the nucleus and activate the expression of many target genes, including STAT1 itself. In parallel, the stability of STAT1 target transcripts is prolonged and enhanced by the loss of hCAF1 deadenylase activity.
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RNA Turnover and Surveillance

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