Organisms with alternative genetic codes resolve unassigned codons via mistranslation and ribosomal rescue

Author:

Ma Natalie Jing12ORCID,Hemez Colin F23ORCID,Barber Karl W24ORCID,Rinehart Jesse24,Isaacs Farren J12ORCID

Affiliation:

1. Department of Molecular, Cellular & Developmental Biology, Yale University, New Haven, United States

2. Systems Biology Institute, Yale University, West Haven, United States

3. Department of Biomedical Engineering, Yale University, New Haven, United States

4. Department of Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, United States

Abstract

Organisms possessing genetic codes with unassigned codons raise the question of how cellular machinery resolves such codons and how this could impact horizontal gene transfer. Here, we use a genomically recoded Escherichia coli to examine how organisms address translation at unassigned UAG codons, which obstruct propagation of UAG-containing viruses and plasmids. Using mass spectrometry, we show that recoded organisms resolve translation at unassigned UAG codons via near-cognate suppression, dramatic frameshifting from at least −3 to +19 nucleotides, and rescue by ssrA-encoded tmRNA, ArfA, and ArfB. We then demonstrate that deleting tmRNA restores expression of UAG-ending proteins and propagation of UAG-containing viruses and plasmids in the recoded strain, indicating that tmRNA rescue and nascent peptide degradation is the cause of impaired virus and plasmid propagation. The ubiquity of tmRNA homologs suggests that genomic recoding is a promising path for impairing horizontal gene transfer and conferring genetic isolation in diverse organisms.

Funder

Defense Advanced Research Projects Agency

U.S. Department of Energy

National Institutes of Health

National Science Foundation

Gruber Foundation

Arnold and Mabel Beckman Foundation

DuPont

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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