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Nonsense-mediated mRNA decay (NMD), the destabilization of an otherwise stable mRNA by premature translation termination, is a conserved quality control pathway that exemplifies the interdependence of mRNA decay and protein synthesis. Our research seeks to: i) define, and exploit for therapeutic purposes, the mechanistic differences between premature and normal translation termination, ii) elucidate the functions of Upf1, Upf2, and Upf3, the ribosome-associated central regulators of NMD, and iii) determine the mechanism of decapping activation by Upf1 and other decapping activators.