The abundance of the mRNA for human triosephosphate isomerase (TPI) is decreased to 20-30% of normal by frameshift and nonsense mutations that prematurely terminate translation within the first three-quarters of the reading frame. The decrease has been shown to be attributable to a reduced level of TPI mRNA that copurifies with nuclei. Given that the translational reading frame of an mRNA is assessed in the cytoplasm during protein synthesis, cytoplasmic and nuclear RNA processes may be linked. Alternatively, a nuclear mechanism may exist whereby in-frame nonsense codons can be identified. To differentiate between these two possibilities, two distinct modulators of protein synthesis have been tested for the ability to influence the nonsense-codon-mediated reduction in the mRNA level. (i) A suppressor tRNA, which acts in trans to suppress an amber nonsense codon within TPI mRNA, and (ii) a hairpin structure in the 5' untranslated region of TPI mRNA, which acts exclusively in cis to inhibit initiation of TPI mRNA translation, were found, individually, and to a greater extent, together, to abrogate the decrease in mRNA. These results show that tRNA and ribosomes coordinately mediate the effect of a nonsense codon on the level of newly synthesized TPI mRNA. We suggest that the premature termination of TPI mRNA translation in the cytoplasm can reduce the level of TPI mRNA that fractionates with nuclei.