Gene expression is regulated during both the synthesis and the decay of mRNAs. Various pathways of cytoplasmic mRNA decay exist. These include ARE-mediated decay, miRNA-Mediated mRNA decay, Nonsense-Mediated mRNA decay (NMD), and the recently discovered Staufen-Mediated mRNA decay (SMD) (1). We want to understand the interplay of Staufen1 (Stau1), a dsRNA-binding protein, with a key mediator of mRNA decay, the Upf1 helicase, as they come together on an mRNA substrate. To do so, we will integrate small angle scattering, biophysical and biochemical analyses with electron microscopy studies. The proposed work will provide unique mechanistic insights into an important and medically relevant mechanism of gene expression regulation in humans.