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. Rent1 (also designated regulator of nonsense transcripts and HUpf1) contains an N-terminal zinc finger-like domain, NTPase domains and a region comprised of domains that define Rent1 as a superfamily group I helicase. Rent1 protein has nucleic-acid-dependent ATPase activity and 5' to 3' helicase activity. In addition, Rent1 is an RNA-binding protein whose activity is modulated by ATP and directly interacts with Rent2, which is a mammalian homolog of Upf2p. Two mammalian orthologs to Upf3p, Rent3a and Rent3b, are encoded by two separate genes. Rent3b (also known as Rent3X) is encoded by a X-linked gene and localizes primarily to the nucleus, while Rent 1 and Rent 2 localize primarily in the cytoplasm. Specific Rent3 protein interactions with Y14 and spliced mRNA suggest Rent3a and Rent3b serve as a link between splicing and NMD in the cytoplasm.