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Cellular heterogeneity in DNA alkylation repair increases population genetic plasticity
DNA repair mechanisms fulfil a dual role, as they are essential for cell survival and genome maintenance. Here, we studied how cells regulate the interplay between DNA repair and mutation. We focused on the adaptive response that increases the resistance of Escherichia coli cells to DNA alkylation d...
Autores principales: | , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8643705/ https://www.ncbi.nlm.nih.gov/pubmed/34850170 http://dx.doi.org/10.1093/nar/gkab1143 |
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author | Vincent, Maxence S Uphoff, Stephan |
author_facet | Vincent, Maxence S Uphoff, Stephan |
author_sort | Vincent, Maxence S |
collection | PubMed |
description | DNA repair mechanisms fulfil a dual role, as they are essential for cell survival and genome maintenance. Here, we studied how cells regulate the interplay between DNA repair and mutation. We focused on the adaptive response that increases the resistance of Escherichia coli cells to DNA alkylation damage. Combination of single-molecule imaging and microfluidic-based single-cell microscopy showed that noise in the gene activation timing of the master regulator Ada is accurately propagated to generate a distinct subpopulation of cells in which all proteins of the adaptive response are essentially absent. Whereas genetic deletion of these proteins causes extreme sensitivity to alkylation stress, a temporary lack of expression is tolerated and increases genetic plasticity of the whole population. We demonstrated this by monitoring the dynamics of nascent DNA mismatches during alkylation stress as well as the frequency of fixed mutations that are generated by the distinct subpopulations of the adaptive response. We propose that stochastic modulation of DNA repair capacity by the adaptive response creates a viable hypermutable subpopulation of cells that acts as a source of genetic diversity in a clonal population. |
format | Online Article Text |
id | pubmed-8643705 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-86437052021-12-06 Cellular heterogeneity in DNA alkylation repair increases population genetic plasticity Vincent, Maxence S Uphoff, Stephan Nucleic Acids Res Genome Integrity, Repair and Replication DNA repair mechanisms fulfil a dual role, as they are essential for cell survival and genome maintenance. Here, we studied how cells regulate the interplay between DNA repair and mutation. We focused on the adaptive response that increases the resistance of Escherichia coli cells to DNA alkylation damage. Combination of single-molecule imaging and microfluidic-based single-cell microscopy showed that noise in the gene activation timing of the master regulator Ada is accurately propagated to generate a distinct subpopulation of cells in which all proteins of the adaptive response are essentially absent. Whereas genetic deletion of these proteins causes extreme sensitivity to alkylation stress, a temporary lack of expression is tolerated and increases genetic plasticity of the whole population. We demonstrated this by monitoring the dynamics of nascent DNA mismatches during alkylation stress as well as the frequency of fixed mutations that are generated by the distinct subpopulations of the adaptive response. We propose that stochastic modulation of DNA repair capacity by the adaptive response creates a viable hypermutable subpopulation of cells that acts as a source of genetic diversity in a clonal population. Oxford University Press 2021-11-25 /pmc/articles/PMC8643705/ /pubmed/34850170 http://dx.doi.org/10.1093/nar/gkab1143 Text en © The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Genome Integrity, Repair and Replication Vincent, Maxence S Uphoff, Stephan Cellular heterogeneity in DNA alkylation repair increases population genetic plasticity |
title | Cellular heterogeneity in DNA alkylation repair increases population genetic plasticity |
title_full | Cellular heterogeneity in DNA alkylation repair increases population genetic plasticity |
title_fullStr | Cellular heterogeneity in DNA alkylation repair increases population genetic plasticity |
title_full_unstemmed | Cellular heterogeneity in DNA alkylation repair increases population genetic plasticity |
title_short | Cellular heterogeneity in DNA alkylation repair increases population genetic plasticity |
title_sort | cellular heterogeneity in dna alkylation repair increases population genetic plasticity |
topic | Genome Integrity, Repair and Replication |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8643705/ https://www.ncbi.nlm.nih.gov/pubmed/34850170 http://dx.doi.org/10.1093/nar/gkab1143 |
work_keys_str_mv | AT vincentmaxences cellularheterogeneityindnaalkylationrepairincreasespopulationgeneticplasticity AT uphoffstephan cellularheterogeneityindnaalkylationrepairincreasespopulationgeneticplasticity |