Chapter 27 : DNA Replication in

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The transfer of genetic material through successive generations is essential to the survival and evolution of all living organisms, including bacteria. As causative agent of tuberculosis (TB), must complete successive cycles of transmission, infection, and disease in order to maintain a viable presence in the human population. And, like other pathogens ( ), is faced with the extra problem of regulating DNA replication, chromosomal segregation, and cell division while residing in diverse anatomical and cellular loci within its human host—including extra- and intracellular compartments ( ). Therefore, in addition to the metabolic challenges faced during infection of dynamic and often hostile environments ( ), is likely to encounter multiple stresses that are directly or indirectly genotoxic ( ). In patients with active TB disease, these stresses might arise from host-derived antimicrobial immune effectors, generation of toxic by-products from host and/or mycobacterial metabolism, changes in intracellular redox potential as a function of shifts in metabolic activity, pH, or oxygen availability, or even exposure to anti-TB drugs. However, given that the number of active TB cases (although devastatingly high in absolute terms) is small relative to the total number of estimated infections ( ), an additional feature of is the ability of infecting bacilli to persist for decades in a poorly understood subclinical state ( ), in some cases reactivating decades later to cause postprimary TB ( ). Under these conditions, DNA replication and repair pathways are predicted to be essential for preserving the genetic content and viability of bacilli located in lesions characterized by different states of immune activation at various stages throughout the disease cycle ( ).

Citation: Ditse Z, Lamers M, Warner D. 2017. DNA Replication in , p 581-606. In Jacobs, Jr. W, McShane H, Mizrahi V, Orme I (ed), Tuberculosis and the Tubercle Bacillus, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.TBTB2-0027-2016
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Figure 1

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 ( ). 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.

Citation: Ditse Z, Lamers M, Warner D. 2017. DNA Replication in , p 581-606. In Jacobs, Jr. W, McShane H, Mizrahi V, Orme I (ed), Tuberculosis and the Tubercle Bacillus, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.TBTB2-0027-2016
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Image of Figure 2
Figure 2

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

Citation: Ditse Z, Lamers M, Warner D. 2017. DNA Replication in , p 581-606. In Jacobs, Jr. W, McShane H, Mizrahi V, Orme I (ed), Tuberculosis and the Tubercle Bacillus, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.TBTB2-0027-2016
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Figure 3

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.

Citation: Ditse Z, Lamers M, Warner D. 2017. DNA Replication in , p 581-606. In Jacobs, Jr. W, McShane H, Mizrahi V, Orme I (ed), Tuberculosis and the Tubercle Bacillus, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.TBTB2-0027-2016
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Figure 4

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 ( ). 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.

Citation: Ditse Z, Lamers M, Warner D. 2017. DNA Replication in , p 581-606. In Jacobs, Jr. W, McShane H, Mizrahi V, Orme I (ed), Tuberculosis and the Tubercle Bacillus, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.TBTB2-0027-2016
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