In eukaryotes, it is essential to have the ability to detect and degrade transcripts that lack full coding potential. Nonsense-mediated RNA decay (NMD) protects the organism by avoiding the translation of truncated peptides with dominant negative or deleterious gain-of-function potential. Rent1, a mammalian ortholog of Upflp, is essential for embryonic viability (1–3). Rent1 (also designated regulator of nonsense transcripts and HUpf1) contains an N-terminal zinc finger-like domain, NTPase d