Transcripts harboring premature signals for translation termination are 
recognized and rapidly degraded by eukaryotic cells through a pathway known as 
nonsense-mediated mRNA decay (NMD). In addition to protecting cells by 
preventing the translation of potentially deleterious truncated peptides, 
studies have suggested that NMD plays a broader role in the regulation of the 
steady-state levels of physiologic transcripts. In Saccharomyces cerevisiae, 
three trans-acting factors (Upf1p to Upf3p) are required for NMD. Orthologues of 
Upf1p have been identified in numerous species, showing that the NMD machinery, 
at least in part, is conserved through evolution. In this study, we demonstrate 
additional functional conservation of the NMD pathway through the identification 
of Upf2p homologues in Schizosaccharomyces pombe and humans (rent2). Disruption 
of S. pombe UPF2 established that this gene is required for NMD in fission 
yeast. rent2 was demonstrated to interact directly with rent1, a known 
trans-effector of NMD in mammalian cells. Additionally, fragments of rent2 were 
shown to possess nuclear targeting activity, although the native protein 
localizes to the cytoplasmic compartment. Finally, novel functional domains of 
Upf2p and rent2 with homology to eukaryotic initiation factor 4G (eIF4G) and 
other translational regulatory proteins were identified. Directed mutations 
within these so-called eIF4G homology (4GH) domains were sufficient to abolish 
the function of S. pombe Upf2p. Furthermore, using the two-hybrid system, we 
obtained evidence for direct interaction between rent2 and human eIF4AI and 
Sui1, both components of the translation initiation complex. Based on these 
findings, a novel model in which Upf2p and rent2 effects decreased translation 
and accelerated decay of nonsense transcripts through competitive interactions 
with eIF4G-binding partners is proposed.