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Open AccessArticle

Stimulation of Replication Template-Switching by DNA-Protein Crosslinks

Department of Biology and Rosenstiel Basic Medical Science Research Center, Brandeis University, Waltham, MA 02454-9110, USA
Author to whom correspondence should be addressed.
These authors contributed equally to the work.
Genes 2019, 10(1), 14;
Received: 31 October 2018 / Revised: 10 December 2018 / Accepted: 12 December 2018 / Published: 27 December 2018
(This article belongs to the Special Issue Chromosome Replication and Genome Integrity)
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 (5-azaC) is a potent mutagen for template-switching. This effect is dependent on DNA cytosine methylase (Dcm), implicating the Dcm-DNA covalent complex trapped by 5-azaC as the initiator for mutagenesis. The leading strand of replication is more mutable than the lagging strand, which can be explained by blocks to the replicative helicase and/or fork regression. We find that template-switch mutagenesis induced by 5-azaC does not require double strand break repair via RecABCD; the ability to induce the SOS response is anti-mutagenic. 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 with similar genetic properties. 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. View Full-Text
Keywords: DNA replication; DNA repair; genetic recombination; mutagenesis DNA replication; DNA repair; genetic recombination; mutagenesis
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MDPI and ACS Style

Laranjo, L.T.; Klaric, J.A.; Pearlman, L.R.; Lovett, S.T. Stimulation of Replication Template-Switching by DNA-Protein Crosslinks. Genes 2019, 10, 14.

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