Template-switching during replication fork repair in bacteria

Lovett, Susan

doi:10.1016/j.dnarep.2017.06.014

Cited by 48 publications

(47 citation statements)

References 120 publications

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“…After by-passing the structural hurdle, replication would continue back on the heavy-strand template. This so-called templateswitching mechanism ( Figure 5B) is well documented in various organisms (Giannattasio et al, 2014;Lovett, 2017), and could take place in mitochondria by the recently reported strand-exchange activity of Twinkle (Sen et al, 2016). Template-switching typically results in the accumulation of catenated circular DNA molecules (Giannattasio et al, 2014), which was in fact observed along with mtDNA deletions in our study on the effects of Twinkle overexpression in fly cells (Ciesielski et al, 2018).…”

Section: What Exactly Happens After the Break?supporting

confidence: 76%

Roles of the mitochondrial replisome in mitochondrial DNA deletion formation

2020

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Mitochondrial DNA (mtDNA) deletions are a common cause of human mitochondrial diseases. Mutations in the genes encoding components of the mitochondrial replisome, such as DNA polymerase gamma (Pol g) and the mtDNA helicase Twinkle, have been associated with the accumulation of such deletions and the development of pathological conditions in humans. Recently, we demonstrated that changes in the level of wild-type Twinkle promote mtDNA deletions, which implies that not only mutations in, but also dysregulation of the stoichiometry between the replisome components is potentially pathogenic. The mechanism(s) by which alterations to the replisome function generate mtDNA deletions is(are) currently under debate. It is commonly accepted that stalling of the replication fork at sites likely to form secondary structures precedes the deletion formation. The secondary structural elements can be bypassed by the replication-slippage mechanism. Otherwise, stalling of the replication fork can generate single-and double-strand breaks, which can be repaired through recombination leading to the elimination of segments between the recombination sites. Here, we discuss aberrances of the replisome in the context of the two debated outcomes, and suggest new mechanistic explanations based on replication restart and template switching that could account for all the deletion types reported for patients.

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Section: What Exactly Happens After the Break?supporting

confidence: 76%

Roles of the mitochondrial replisome in mitochondrial DNA deletion formation

2020

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“…The abundance of IRs in genomes implies a mechanism, acting to maintain perfect IRs in genomes. The mechanism of template switching that was reported in experimental systems to homogenize IR arms during replication is the best known mechanism to explain the enrichment of perfect IRs in genomes ( Lovett 2017 ).…”

Section: Discussionmentioning

confidence: 99%

The Prevalence and Evolutionary Conservation of Inverted Repeats in Proteobacteria

Lavi

Karin

Pupko

et al. 2018

Genome Biology and Evolution

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Perfect short inverted repeats (IRs) are known to be enriched in a variety of bacterial and eukaryotic genomes. Currently, it is unclear whether perfect IRs are conserved over evolutionary time scales. In this study, we aimed to characterize the prevalence and evolutionary conservation of IRs across 20 proteobacterial strains. We first identified IRs in Escherichia coli K-12 substr MG1655 and showed that they are overabundant. We next aimed to test whether this overabundance is reflected in the conservation of IRs over evolutionary time scales. To this end, for each perfect IR identified in E. coli MG1655, we collected orthologous sequences from related proteobacterial genomes. We next quantified the evolutionary conservation of these IRs, that is, the presence of the exact same IR across orthologous regions. We observed high conservation of perfect IRs: out of the 234 examined orthologous regions, 145 were more conserved than expected, which is statistically significant even after correcting for multiple testing. Our results together with previous experimental findings support a model in which imperfect IRs are corrected to perfect IRs in a preferential manner via a template switching mechanism.

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“…Mutations arising in imperfect inverted repeats, "quasipalindromes (QPs)" have been noted in a wide range of organisms, from bacteria to humans (reviewed in [16,17]). As has been shown for both yeast and bacteria, these sites constitute hotspots for mutation [39,40].…”

Section: Discussionmentioning

confidence: 99%

“…Because DPCs lead to replication stalling [3,4,15], we suspected that certain classes of mutation would also be elevated. Copy-number variation and certain templated-genetic mutations are triggered by misalignments of the nascent strand with a template strand during DNA replication (reviewed in [16,17]). The likelihood of these events is enhanced by difficulties in DNA replication.…”

Section: Introductionmentioning

confidence: 99%

Stimulation of Replication Template-Switching by DNA-Protein Crosslinks

Laranjo¹,

Klaric²,

Lovett³

2018

Preprint

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Covalent DNA protein crosslinks (DPCs) are common lesions that block replication. We examine here the consequence of DPCs on mutagenesis involving replicational template-switch reactions in Escherichia coli. 5-azacytidine (5azaC) is a potent mutagen for template-switching, dependent on DNA cytosine methylase (Dcm), implicating the trapped Dcm-DNA covalent complex as the initiator for mutagenesis. The leading strand of replication is more mutable than the lagging strand, explained by blocks to the replicative helicase and/or fork regression. We find that template-switch mutagenesis induced by 5-azaC does not require DSB repair via RecABCD. The ability to induce the SOS response is anti-mutagenic by an unknown mechanism. Mutants in recB, but not recA, exhibit high constitutive rates of template-switching and we suggest that RecBCD-mediated DNA degradation prevents template-switching associated with fork regression. A mutation in the DnaB fork helicase also promotes high levels of template-switching. We also find that other DPC-inducers, formaldehyde (a non-specific crosslinker) and ciprofloxacin (a topoisomerase II poison) are also strong mutagens for template-switching. Induction of mutations and genetic rearrangements that occur by template-switching may constitute a previously unrecognized component of the genotoxicity and genetic instability promoted by DPCs.

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Template-switching during replication fork repair in bacteria

Cited by 48 publications

References 120 publications

Roles of the mitochondrial replisome in mitochondrial DNA deletion formation

Roles of the mitochondrial replisome in mitochondrial DNA deletion formation

The Prevalence and Evolutionary Conservation of Inverted Repeats in Proteobacteria

Stimulation of Replication Template-Switching by DNA-Protein Crosslinks

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