Role of Base Excision Repair in Listeria monocytogenes DNA Stress Survival During Infections

2020 ◽  
Author(s):  
Juan Zhang ◽  
Shuyi Wang ◽  
Tjakko Abee ◽  
Stijn van der Veen
Keyword(s):  
Listeria Monocytogenes ◽  
Mouse Model ◽  
Base Excision Repair ◽  
Bacterial Infections ◽  
Excision Repair ◽  
Deletion Mutants ◽  
Dna Glycosylases ◽  
Repair Mechanisms ◽  
Base Excision

Abstract Background Base excision repair (BER), consisting mostly of lesion-specific DNA glycosylases and apurinic/apyrimidinic (AP) endonucleases, is one of the most important DNA repair mechanisms for repair of single nucleobase lesions generated by reactive oxygen and nitrogen species as part of an immune response against bacterial infections. However, few studies have addressed the contribution of BER to bacterial virulence and Listeria monocytogenes BER has thus far remained completely uncharacterized. Methods Analysis of the L. monocytogenes EGDe genome identified 7 DNA glycosylases (MutM, MutY, Nth, Tag, Mpg, Ung, and Ung2) and 2 apurinic/apyrimidinic endonucleases (Xth and Nfo) as part of BER. Markerless in-frame deletion mutants were generated for all 9 genes, and mutants were tested for DNA damage survival, mutagenesis, and the ability to colonize a mouse model of infection. Results Distinct lesion-specific phenotypes were identified for all deletion mutants. Importantly, the Δnth, ΔmutY, and Δnfo mutants were significantly attenuated for virulence in the mouse model and showed much lower colonization of the liver and spleen or were unable to compete with the wild-type strain during in vivo competition assays. Conclusions Our results highlight the importance of BER for L. monocytogenes virulence and survival of DNA-damaging insults during host colonization.

scholarly journals Effect of DNA Glycosylases OGG1 and Neil1 on Oxidized G-Rich Motif in the KRAS Promoter

2021 ◽  
Vol 22 (3) ◽  
pp. 1137
Author(s):  
Annalisa Ferino ◽  
Luigi E. Xodo
Keyword(s):  
Oxidative Stress ◽  
Base Excision Repair ◽  
Excision Repair ◽  
Start Site ◽  
Dna Glycosylases ◽  
Repair Pathway ◽  
Transcription Start ◽  
G Quadruplex ◽  
Base Excision ◽  
Regulatory Functions

The promoter of the Kirsten ras (KRAS) proto-oncogene contains, upstream of the transcription start site, a quadruplex-forming motif called 32R with regulatory functions. As guanine under oxidative stress can be oxidized to 8-oxoguanine (8OG), we investigated the capacity of glycosylases 8-oxoguanine glycosylase (OGG1) and endonuclease VIII-like 1 (Neil1) to excise 8OG from 32R, either in duplex or G-quadruplex (G4) conformation. We found that OGG1 efficiently excised 8OG from oxidized 32R in duplex but not in G4 conformation. By contrast, glycosylase Neil1 showed more activity on the G4 than the duplex conformation. We also found that the excising activity of Neil1 on folded 32R depended on G4 topology. Our data suggest that Neil1, besides being involved in base excision repair pathway (BER), could play a role on KRAS transcription.

scholarly journals The Brucella abortus xthA-1 Gene Product Participates in Base Excision Repair and Resistance to Oxidative Killing but Is Not Required for Wild-Type Virulence in the Mouse Model

2006 ◽  
Vol 188 (4) ◽  
pp. 1295-1300 ◽  
Author(s):  
Michael L. Hornback ◽  
R. Martin Roop
Keyword(s):  
Mouse Model ◽  
Oxidative Damage ◽  
Gene Product ◽  
Base Excision Repair ◽  
Brucella Abortus ◽  
Excision Repair ◽  
Wild Type ◽  
Exonuclease Iii ◽  
Increased Sensitivity ◽  
Base Excision

ABSTRACT Exonuclease III, encoded by the xthA gene, plays a central role in the base excision pathway of DNA repair in bacteria. Studies with Escherichia coli xthA mutants have also shown that exonuclease III participates in the repair of oxidative damage to DNA. An isogenic xthA-1 mutant (designated CAM220) derived from virulent Brucella abortus 2308 exhibited increased sensitivity to the alkylating agent methyl methanesulfonate (MMS) compared to the parent strain. In contrast, 2308 and the isogenic xthA-1 mutant displayed similar levels of resistance to the DNA cross-linker mitomycin C. These phenotypic properties are those that would be predicted for a strain defective in base excision repair. The B. abortus xthA-1 mutant also displayed reduced resistance to killing by H2O2 and the ONOO−-generating compound 3-morpholinosydnonimine (SIN-1) compared to strain 2308, indicating that the xthA-1 gene product participates in protecting B. abortus 2308 from oxidative damage. Introducing a plasmid-borne copy of the parental xthA-1 gene into CAM220 restored wild-type resistance of this mutant to MMS, H2O2, and SIN-1. Although the B. abortus xthA-1 mutant exhibited increased sensitivity to oxidative killing compared to the parental strain in laboratory assays, CAM220 and 2308 displayed equivalent spleen colonization profiles in BALB/c mice through 8 weeks postinfection and equivalent intracellular survival and replication profiles in cultured murine macrophages. Thus, although the xthA-1 gene product participates in base excision repair and resistance to oxidative killing in B. abortus 2308, XthA-1 is not required for wild-type virulence of this strain in the mouse model.

XRCC1 interactions with multiple DNA glycosylases: A model for its recruitment to base excision repair

DNA Repair ◽  
2005 ◽  
Vol 4 (7) ◽  
pp. 826-835 ◽  
Author(s):  
Anna Campalans ◽  
Stéphanie Marsin ◽  
Yusaku Nakabeppu ◽  
Timothy R. O’Connor ◽  
Serge Boiteux ◽  
...  
Keyword(s):  
Base Excision Repair ◽  
Excision Repair ◽  
Dna Glycosylases ◽  
Base Excision

scholarly journals PARP1 and PARP2 stabilise replication forks at base excision repair intermediates through Fbh1-dependent Rad51 regulation

2018 ◽  
Author(s):  
George E. Ronson ◽  
Ann Liza Piberger ◽  
Martin R. Higgs ◽  
Anna L. Olsen ◽  
Grant S. Stewart ◽  
...  
Keyword(s):  
Base Excision Repair ◽  
Damage Tolerance ◽  
Excision Repair ◽  
Replication Forks ◽  
Strand Breaks ◽  
Single Strand Breaks ◽  
Dna Base ◽  
Repair Mechanisms ◽  
Base Excision

AbstractPARP1 regulates the repair of DNA single strand breaks (SSBs) generated directly, or during base excision repair (BER). However, the role of PARP2 in these and other repair mechanisms is unknown. Here, we report a requirement for PARP2 in stabilising replication forks that encounter BER intermediates through Fbh1-dependent regulation of Rad51. Whilst PARP2 is dispensable for tolerance of cells to SSBs or homologous recombination dysfunction, it is redundant with PARP1 in BER. Therefore, combined disruption of PARP1 and PARP2 leads to defective BER, resulting in elevated levels of replication associated DNA damage due to an inability to stabilise Rad51 at damaged replication forks and prevent uncontrolled DNA resection. Together, our results demonstrate how PARP1 and PARP2 regulate two independent, but intrinsically linked aspects of DNA base damage tolerance by promoting BER directly, and through stabilising replication forks that encounter BER intermediates.

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