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Oxidative stress drives mutagenesis through transcription coupled repair in bacteria

View ORCID ProfileJuan Carvajal-Garcia, Ariana N. Samadpour, Angel J. Hernandez Viera, Houra Merrikh
doi: https://doi.org/10.1101/2022.06.28.497968
Juan Carvajal-Garcia
1Vanderbilt University School of Medicine, Department of Biochemistry, Nashville, TN 37232, USA
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  • ORCID record for Juan Carvajal-Garcia
Ariana N. Samadpour
2Department of Microbiology, University of Washington, Seattle, WA 98195, USA
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Angel J. Hernandez Viera
1Vanderbilt University School of Medicine, Department of Biochemistry, Nashville, TN 37232, USA
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Houra Merrikh
1Vanderbilt University School of Medicine, Department of Biochemistry, Nashville, TN 37232, USA
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  • For correspondence: houra.merrikh@vanderbilt.edu
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Abstract

In bacteria, mutations lead to the evolution of antibiotic resistance, which is one the main public health problems of the 21st century. Therefore, determining which cellular processes most frequently contribute to mutagenesis, especially in cells that have not been exposed to exogenous DNA damage, is critical. Here, we show that endogenous oxidative stress is a key driver of mutagenesis and the subsequent development of antibiotic resistance. This is the case for all classes of antibiotics tested and across highly divergent species, including patient-derived strains. We show that the transcription-coupled repair pathway, which uses the nucleotide excision repair proteins (TC-NER), is responsible for endogenous oxidative stress-dependent mutagenesis and subsequent evolution. This strongly suggests that a majority of mutations arise through transcription-associated processes rather than the replication fork. In addition to determining that the NER proteins play a critical role in mutagenesis and evolution, we also identify the DNA polymerases responsible for this process. Our data strongly suggest that cooperation between three different mutagenic DNA polymerases, likely at the last step of TC-NER, is responsible for mutagenesis and evolution. Overall, our work identifies that a highly conserved pathway drives mutagenesis due to endogenous oxidative stress, which has broad implications for all diseases of evolution, including antibiotic resistance development.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • We have re-organized the manuscript to emphasize the role of oxidative stress in mutagenesis and evolution. We have increased the number of antibiotics and species tested, and we observe a similar role for oxidative stress in the evolution of resistance. We generated a separation of function mutant on PolA to directly test whether the interaction between it and PolY1/2 plays a role in mutagenesis.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.
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Posted January 13, 2023.
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Oxidative stress drives mutagenesis through transcription coupled repair in bacteria
Juan Carvajal-Garcia, Ariana N. Samadpour, Angel J. Hernandez Viera, Houra Merrikh
bioRxiv 2022.06.28.497968; doi: https://doi.org/10.1101/2022.06.28.497968
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Oxidative stress drives mutagenesis through transcription coupled repair in bacteria
Juan Carvajal-Garcia, Ariana N. Samadpour, Angel J. Hernandez Viera, Houra Merrikh
bioRxiv 2022.06.28.497968; doi: https://doi.org/10.1101/2022.06.28.497968

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