Environment modulates protein heterogeneity through transcriptional and translational stop codon readthrough

Maria Luisa Romero Romero (), Jonas Poehls, Anastasiia Kirilenko, Doris Richter, Tobias Jumel, Anna Shevchenko and Agnes Toth-Petroczy ()
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Maria Luisa Romero Romero: Max Planck Institute of Molecular Cell Biology and Genetics
Jonas Poehls: Max Planck Institute of Molecular Cell Biology and Genetics
Anastasiia Kirilenko: Max Planck Institute of Molecular Cell Biology and Genetics
Doris Richter: Max Planck Institute of Molecular Cell Biology and Genetics
Tobias Jumel: Max Planck Institute of Molecular Cell Biology and Genetics
Anna Shevchenko: Max Planck Institute of Molecular Cell Biology and Genetics
Agnes Toth-Petroczy: Max Planck Institute of Molecular Cell Biology and Genetics

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract Stop codon readthrough events give rise to longer proteins, which may alter the protein’s function, thereby generating short-lasting phenotypic variability from a single gene. In order to systematically assess the frequency and origin of stop codon readthrough events, we designed a library of reporters. We introduced premature stop codons into mScarlet, which enabled high-throughput quantification of protein synthesis termination errors in E. coli using fluorescent microscopy. We found that under stress conditions, stop codon readthrough may occur at rates as high as 80%, depending on the nucleotide context, suggesting that evolution frequently samples stop codon readthrough events. The analysis of selected reporters by mass spectrometry and RNA-seq showed that not only translation but also transcription errors contribute to stop codon readthrough. The RNA polymerase was more likely to misincorporate a nucleotide at premature stop codons. Proteome-wide detection of stop codon readthrough by mass spectrometry revealed that temperature regulated the expression of cryptic sequences generated by stop codon readthrough in E. coli. Overall, our findings suggest that the environment affects the accuracy of protein production, which increases protein heterogeneity when the organisms need to adapt to new conditions.

Date: 2024
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DOI: 10.1038/s41467-024-48387-x

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