Human DDX6 effects miRNA-mediated gene silencing via direct binding to CNOT1 |
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Authors: | Christopher Rouya Nadeem Siddiqui Masahiro Morita Thomas F. Duchaine Marc R. Fabian Nahum Sonenberg |
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Affiliation: | 1.Department of Biochemistry, McGill University, Montreal, Quebec, H3G 1Y6, Canada;2.Goodman Cancer Research Centre, McGill University, Montreal, Quebec, H3A 1A3, Canada;3.Lady Davis Institute for Medical Research, SMBD-Jewish General Hospital, McGill University, Montreal, Quebec H3T 1E2, Canada |
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Abstract: | MicroRNAs (miRNAs) play critical roles in a variety of biological processes through widespread effects on protein synthesis. Upon association with the miRNA-induced silencing complex (miRISC), miRNAs repress target mRNA translation and accelerate mRNA decay. Degradation of the mRNA is initiated by shortening of the poly(A) tail by the CCR4–NOT deadenylase complex followed by the removal of the 5′ cap structure and exonucleolytic decay of the mRNA. Here, we report a direct interaction between the large scaffolding subunit of CCR4–NOT, CNOT1, with the translational repressor and decapping activator protein, DDX6. DDX6 binds to a conserved CNOT1 subdomain in a manner resembling the interaction of the translation initiation factor eIF4A with eIF4G. Importantly, mutations that disrupt the DDX6–CNOT1 interaction impair miRISC-mediated gene silencing in human cells. Thus, CNOT1 facilitates recruitment of DDX6 to miRNA-targeted mRNAs, placing DDX6 as a downstream effector in the miRNA silencing pathway. |
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Keywords: | microRNA, deadenylation, CCR4– NOT, DDX6, decapping, mRNA decay |
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