miRNA-mediated repression affects a wide range of biological processes including development and human pathologies. The GW182 protein is a key component of miRNA repression complex, recruited by Argonaute and functioning downstream to repress translation and accelerate mRNA degradation, but little is known about how GW182 proteins act. Using both tethered function and complementation assays, we identify three independent domains of the
DrosophilaGW182 protein (also termed Gawky) that are sufficient to repress mRNA. Each of these domains also functions independently of poly(A) tails. These results indicate that miRNA-mediated repression is facilitated by multiple domains of GW182.