Selective translational repression of truncated proteins from frameshift mutation-derived mRNAs in tumors

Tae You Kwon, Shan Li Long, Nam Gyun Kim, Ju Kang Hyun, Hye Koh Kwi, Yong Joon Chwae, Mi Kim Kyoung, Ki Kim Yoon, Mi Park Sung, Key Jang Sung, Hoguen Kim

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1098-1109
Number of pages12
JournalPLoS biology
Volume5
Issue number5
DOIs
StatePublished - May 2007

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Agricultural and Biological Sciences(all)

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    Kwon, T. Y., Long, S. L., Kim, N. G., Hyun, J. K., Kwi, H. K., Chwae, Y. J., Kyoung, M. K., Yoon, K. K., Sung, M. P., Sung, K. J., & Kim, H. (2007). Selective translational repression of truncated proteins from frameshift mutation-derived mRNAs in tumors. PLoS biology, 5(5), 1098-1109. https://doi.org/10.1371/journal.pbio.0050109