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DNA Replication in

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  • Authors: Zanele Ditse1, Meindert H. Lamers2, Digby F. Warner3,4
  • Editors: William R. Jacobs Jr.5, Helen McShane6, Valerie Mizrahi7, Ian M. Orme8
    Affiliations: 1: Centre for HIV and STIs, National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg, 2131, South Africa; 2: Medical Research Council Laboratory of Molecular Biology, Cambridge, CB2 0QH United Kingdom; 3: South African Medical Research Council (SAMRC)/National Health Laboratory Services (NHLS)/University of Cape Town (UCT) Molecular Mycobacteriology Research Unit, Department of Science and Technology (DST)/National Research Foundation (NRF) Centre of Excellence for Biomedical TB Research, Department of Pathology, Faculty of Health Sciences, University of Cape Town, Rondebosch 7700, South Africa; 4: Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town; Rondebosch 7700 South Africa; 5: Howard Hughes Medical Institute, Albert Einstein School of Medicine, Bronx, NY 10461; 6: University of Oxford, Oxford OX3 7DQ, United Kingdom; 7: University of Cape Town, Rondebosch 7701, South Africa; 8: Colorado State University, Fort Collins, CO 80523
  • Source: microbiolspec March 2017 vol. 5 no. 2 doi:10.1128/microbiolspec.TBTB2-0027-2016
  • Received 05 August 2016 Accepted 23 January 2017 Published 31 March 2017
  • Meindert H. Lamers, [email protected], or Digby F. Warner, [email protected]
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  • Abstract:

    Faithful replication and maintenance of the genome are essential to the ability of any organism to survive and propagate. For an obligate pathogen such as that has to complete successive cycles of transmission, infection, and disease in order to retain a foothold in the human population, this requires that genome replication and maintenance must be accomplished under the metabolic, immune, and antibiotic stresses encountered during passage through variable host environments. Comparative genomic analyses have established that chromosomal mutations enable to adapt to these stresses: the emergence of drug-resistant isolates provides direct evidence of this capacity, so too the well-documented genetic diversity among lineages across geographic loci, as well as the microvariation within individual patients that is increasingly observed as whole-genome sequencing methodologies are applied to clinical samples and tuberculosis (TB) disease models. However, the precise mutagenic mechanisms responsible for evolution and adaptation are poorly understood. Here, we summarize current knowledge of the machinery responsible for DNA replication in , and discuss the potential contribution of the expanded complement of mycobacterial DNA polymerases to mutagenesis. We also consider briefly the possible role of DNA replication—in particular, its regulation and coordination with cell division—in the ability of to withstand antibacterial stresses, including host immune effectors and antibiotics, through the generation at the population level of a tolerant state, or through the formation of a subpopulation of persister bacilli—both of which might be relevant to the emergence and fixation of genetic drug resistance.

  • Citation: Ditse Z, Lamers M, Warner D. 2017. DNA Replication in . Microbiol Spectrum 5(2):TBTB2-0027-2016. doi:10.1128/microbiolspec.TBTB2-0027-2016.


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Faithful replication and maintenance of the genome are essential to the ability of any organism to survive and propagate. For an obligate pathogen such as that has to complete successive cycles of transmission, infection, and disease in order to retain a foothold in the human population, this requires that genome replication and maintenance must be accomplished under the metabolic, immune, and antibiotic stresses encountered during passage through variable host environments. Comparative genomic analyses have established that chromosomal mutations enable to adapt to these stresses: the emergence of drug-resistant isolates provides direct evidence of this capacity, so too the well-documented genetic diversity among lineages across geographic loci, as well as the microvariation within individual patients that is increasingly observed as whole-genome sequencing methodologies are applied to clinical samples and tuberculosis (TB) disease models. However, the precise mutagenic mechanisms responsible for evolution and adaptation are poorly understood. Here, we summarize current knowledge of the machinery responsible for DNA replication in , and discuss the potential contribution of the expanded complement of mycobacterial DNA polymerases to mutagenesis. We also consider briefly the possible role of DNA replication—in particular, its regulation and coordination with cell division—in the ability of to withstand antibacterial stresses, including host immune effectors and antibiotics, through the generation at the population level of a tolerant state, or through the formation of a subpopulation of persister bacilli—both of which might be relevant to the emergence and fixation of genetic drug resistance.

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A working model of the mycobacterial replisome. Schematic representation of the model replisome consisting of the PolIII core polymerase, the homodimeric β-sliding clamp, the τδδ′ clamp-loader complex, DnaB helicase (red hexamer), DnaG primase (blue), PolI (pink) DNA ligase (purple), and SSB (orange). Recent biochemical evidence suggests that, in , the ε proofreader forms part of the core replicase together with the β and α subunits ( 42 ). As noted in the main text, the precise stoichiometry and architecture of the mycobacterial replisome remain to be established; similarly, it is not known whether the mycobacterial replisome functions as a di- or tripolymerase system, nor whether DnaE2 is able to access the replisome under non-DNA-damaging conditions in the absence of ImuB and ImuA′ accessory factors.

Source: microbiolspec March 2017 vol. 5 no. 2 doi:10.1128/microbiolspec.TBTB2-0027-2016
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Subcomplex division in the bacterial replisome. The replisome contains three catalytic centers: core, clamp loader, and helicase-primase. The core complex and clamp-loader complex assemble into a larger, stable complex termed Pol III*. Together with the β clamp, they form the Pol III holoenzyme. The DnaB helicase and DnaG primase form a transient complex to synthesize primers on the lagging strand. Modified with permission from the , Volume 74 © 2005 by Annual Reviews, http://www.annualreviews.org

Source: microbiolspec March 2017 vol. 5 no. 2 doi:10.1128/microbiolspec.TBTB2-0027-2016
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Structure of the C-family polymerases. Computational model of DnaE1 based on the crystal structure of PolIII. Different domains indicated in separate colors (C-terminal domains not shown). Domain organization in the different polymerase families. The DnaE families are defined by the presence of the C-terminal domains, whereas PolC forms a distinct class where an ε-like exonuclease domain is inserted into the PHP domain.

Source: microbiolspec March 2017 vol. 5 no. 2 doi:10.1128/microbiolspec.TBTB2-0027-2016
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Population heterogeneity as a function of the applied stress. The cartoon summarizes the notion that the degree (or strength) of applied stress might determine the extent of phenotypic heterogeneity within a specific (myco)bacterial population. So, as the applied stress (e.g., genotoxin, antibiotic, nutrient deprivation, pH, oxygen starvation) increases toward a critical point or concentration (which will differ for each stress), the degree of heterogeneity within the population increases. Beyond that critical point (the vertex of the parabola), the result is more likely to be manifest as a general, regulated response at the population level; this has the effect of reducing the extent of heterogeneity within the population. At each extreme (low/absent stress versus high/severe stress), the degree of heterogeneity approaches a minimum. Importantly, for conditions under which both the applied stress and the degree of heterogeneity are low, a small subpopulation of persister cells might enable survival, consistent with the framework proposed by Balaban and colleagues ( 177 ). At the other extreme—high/severe stress, low heterogeneity—any observed tolerance will exist at the population level, and will be mediated by a dominant regulatory mechanism(s), such as the LexA/RecA-dependent SOS response.

Source: microbiolspec March 2017 vol. 5 no. 2 doi:10.1128/microbiolspec.TBTB2-0027-2016
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Components of the bacterial replisome

Source: microbiolspec March 2017 vol. 5 no. 2 doi:10.1128/microbiolspec.TBTB2-0027-2016
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Unique components of the mycobacterial replisome/repair—not present in

Source: microbiolspec March 2017 vol. 5 no. 2 doi:10.1128/microbiolspec.TBTB2-0027-2016

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