Human DDX6 effects miRNA-mediated gene silencing via direct binding to CNOT1

Christopher Rouya, Nadeem Siddiqui, Masahiro Morita, Thomas F. Duchaine, Marc R. Fabian, Nahum Sonenberg

Research output: Contribution to journalArticle

65 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1398-1409
Number of pages12
JournalRNA
Volume20
Issue number9
DOIs
StatePublished - Sep 2014
Externally publishedYes

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Keywords

  • CCR4-NOT
  • DDX6
  • Deadenylation
  • Decapping
  • mRNA decay
  • microRNA

ASJC Scopus subject areas

  • Molecular Biology

Cite this

Rouya, C., Siddiqui, N., Morita, M., Duchaine, T. F., Fabian, M. R., & Sonenberg, N. (2014). Human DDX6 effects miRNA-mediated gene silencing via direct binding to CNOT1. RNA, 20(9), 1398-1409. https://doi.org/10.1261/rna.045302.114