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mi RNA s associate with Argonaute ( AGO ) proteins to silence the expression of  mRNA  targets by inhibiting translation and promoting deadenylation, decapping, and  mRNA  degradation. A current model for silencing suggests that  AGO s mediate these effects through the sequential recruitment of  GW 182 proteins, the  CCR 4– NOT  deadenylase complex and the translational repressor and decapping activator  DDX 6. An alternative model posits that  AGO s repress translation by interfering with  eIF 4A function during 43S ribosomal scanning and that this mechanism is independent of  GW 182 and the  CCR 4– NOT  complex in  Drosophila melanogaster . Here, we show that mi RNA s,  AGO s,  GW 182, the  CCR 4– NOT  complex, and  DDX 6/Me31B repress and degrade polyadenylated  mRNA  targets that are translated via scanning‐independent mechanisms in both human and  Dm  cells. This and additional observations indicate a common mechanism used by these proteins and mi RNA s to mediate silencing. This mechanism does not require  eIF 4A function during ribosomal scanning.

mi RISC and the CCR 4– NOT complex silence mRNA targets independently of 43S ribosomal scanning