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

Version of Record: March 23, 2020
Accepted Manuscript: January 23, 2020

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Insight Mar 23, 2020

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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).

Data availability

Sequencing data have been deposited in GEO under accession number GSE138643.

The following data sets were generated

1. Wangen JR
2. Green R
(2019) Stop Codon Context Influences Genome-Wide Stimulation of Termination Codon Readthrough by Aminoglycosides
NCBI Gene Expression Omnibus, GSE138643.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE138643

Article and author information

Author details

Jamie R Wangen

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

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0001-7008-5749
Rachel Green

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

For correspondence
ragreen@jhmi.edu

Competing interests
Rachel Green, Reviewing editor, eLife.

"This ORCID iD identifies the author of this article:" 0000-0001-9337-2003

Funding

Cystic Fibrosis Foundation (GREEN16G0)

Jamie R Wangen
Rachel Green

National Institutes of Health (T32 GM007445)

Jamie R Wangen

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.