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Preserved in Portico This version is not peer-reviewed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.
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
Biology and Life Sciences, Biochemistry and Molecular Biology
Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Comments (0)
We encourage comments and feedback from a broad range of readers. See criteria for comments and our Diversity statement.
Leave a public commentSend a private comment to the author(s)
* All users must log in before leaving a comment