The nonsense-mediated mRNA decay (NMD) pathway monitors premature translati
on termination and degradess aberrant mRNAs. In yeast, it has been proposed
that a surveillance complex searches 3' of a nonsense codon for a downstre
am sequence element (DSE) associated with RNA-binding proteins. An interact
ion between the complex and the DSE-binding protein(s) triggers NMD. Here w
e describe the identification and characterization of the Hrp1/Nab4 protein
as a DSE-binding factor that activates NMD. Mutations in HRP1 stabilize no
nsense-containing transcripts without affecting the decay of wild-type mRNA
s. Hrp1p binds specifically to a DSE-containing RNA and interacts with Upf1
p, a component of the surveillance complex. A mutation in HRP1 that stabili
zes nonsense-containing mRNAs abolishes its affinity for the DSE and fails
to interact with Upf1p. We present a model describing how Hrp1p marks a tra
nscript for rapid decay.