Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Stimulation of Replication Template-Switching by DNA-Protein Crosslinks

Version 1 : Received: 31 October 2018 / Approved: 2 November 2018 / Online: 2 November 2018 (10:19:18 CET)

A peer-reviewed article of this Preprint also exists.

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. 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.

Journal reference: Genes 2019, 10, 14
DOI: 10.3390/genes10010014

Abstract

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.

Keywords

DNA replication, DNA repair, genetic recombination, mutagenesis

Subject

LIFE SCIENCES, Genetics

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