FIG. 5.
Possible mechanisms by which nonsense codons mediate the decay of TPI mRNA. Each model pertains to newly synthesized, nucleus-associated mRNA, the species that undergoes nonsense-mediated decay. The two models differ at Step 3. According to model 1, once translation initiates on TPI mRNA, if translating ribosomes fail to approximate the junction of the last two exons, then the mRNA is degraded. According to model 2, which seems more likely than model 1, once translation initiates and subsequently terminates ∼50 nt or more upstream of the junction of the last two exons, then a complex that could involve a 40S ribosome, eIF-2-GTP-Met-tRNAiMet, and/or, possibly, other component(s) of the translation termination complex, such as the mammalian homolog to S. cerevisiae Upflp (shown as the filled circle), could scan the mRNA downstream of the termination site. If the scanner reaches the junction of the last two exons or, possibly, any downstream exon-exon junction or the failsafe sequence that functions on behalf of intron 6, then the mRNA is degraded. Translation elongation, i.e., peptide bond formation, is not required for nonsense-mediated decay (47). AUG, initiation codon; ter, premature termination codon; UGA, normal termination codon; 40S and 60S, ribosome subunits. We believe the models for TPI mRNA can be generalized to other mRNAs. To do so, the exon 6–exon 7 junction would be substituted with the 3′-most exon-exon junction and UGA would be substituted with the normal termination codon. Furthermore, the consideration that all exon-exon junctions would be marked and the existence of a failsafe sequence would also pertain.