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Elife. 2020 Jan 23;9. pii: e52611. doi: 10.7554/eLife.52611. [Epub ahead of print]

Stop codon context influences genome-wide stimulation of termination codon readthrough by aminoglycosides.

Author information

1
Department of Molecular Biology and Genetics, Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, United States.

Abstract

Stop codon readthrough (SCR) occurs when the ribosome miscodes at a stop codon. Such readthrough events can be therapeutically desirable when a premature termination codon (PTC) is found in a critical gene. To study SCR in vivo in a genome-wide manner, we treated mammalian cells with aminoglycosides and performed ribosome profiling. We find that in addition to stimulating readthrough of PTCs, aminoglycosides stimulate readthrough of normal termination codons (NTCs) genome-wide. Stop codon identity, the nucleotide following the stop codon, and the surrounding mRNA sequence context all influence the likelihood of SCR. In comparison to NTCs, downstream stop codons in 3'UTRs are recognized less efficiently by ribosomes, suggesting that targeting of critical stop codons for readthrough may be achievable without general disruption of translation termination. Finally, we find that G418-induced miscoding alters gene expression with substantial effects on translation of histone genes, selenoprotein genes, and S-adenosylmethionine decarboxylase (AMD1).

KEYWORDS:

chromosomes; gene expression; human

PMID:
31971508
DOI:
10.7554/eLife.52611
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Conflict of interest statement

JW The other authors declare that no competing interests exist. RG Rachel Green, Reviewing editor, eLife.

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