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Frameshift and nonsense mutations are common in tumors with microsatellite instability, and mRNAs from these mutated genes have premature termination codons (PTCs). Abnormal mRNAs containing PTCs are normally degraded by the nonsense-mediated mRNA decay (NMD) system. However, PTCs located within 50–55 nucleotides of the last exon–exon junction are not recognized by NMD (NMD-irrelevant), and some PTC-containing mRNAs can escape from the NMD system (NMD-escape). We investigated protein expression from NMD-irrelevant and NMD-escape PTC-containing mRNAs by Western blotting and transfection assays. We demonstrated that transfection of NMD-irrelevant PTC-containing genomic DNA of  MARCKS  generates truncated protein. In contrast, NMD-escape PTC-containing versions of  hMSH3  and  TGFBR2  generate normal levels of mRNA, but do not generate detectable levels of protein. Transfection of NMD-escape mutant  TGFBR2  genomic DNA failed to generate expression of truncated proteins, whereas transfection of wild-type  TGFBR2  genomic DNA or mutant PTC-containing  TGFBR2  cDNA generated expression of wild-type protein and truncated protein, respectively. Our findings suggest a novel mechanism of gene expression regulation for PTC-containing mRNAs in which the deleterious transcripts are regulated either by NMD or translational repression.

Selective Translational Repression of Truncated Proteins from Frameshift Mutation-Derived mRNAs in Tumors