DNA Repair and Mutagenesis

Errol, C. Friedberg; Graham, Chris; Siede, Wolfram; Richard, D. Wood; Roger, A. Schultz; Ellenberger, Tom

doi:10.1128/9781555816704

Cited by 1,090 publications

(1,112 citation statements)

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“…Interestingly, the increase in the amount of cleaved LexA was not accompanied by a diminution in the amount of uncleaved LexA observed (lanes 4–6, top band). This suggests re-synthesis of LexA by this point in the SOS response, after 3 h of treatment, as previously observed [40]. Trends similar to that observed in CP9 were also observed in STEC Popeye-1, but in the STEC strain the intact LexA bands were fainter, and disappeared more quickly after ciprofloxacin treatment (Blots not shown).…”

Section: Resultssupporting

confidence: 83%

Zinc blocks SOS-induced antibiotic resistance via inhibition of RecA in Escherichia coli

et al. 2017

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Zinc inhibits the virulence of diarrheagenic E. coli by inducing the envelope stress response and inhibiting the SOS response. The SOS response is triggered by damage to bacterial DNA. In Shiga-toxigenic E. coli, the SOS response strongly induces the production of Shiga toxins (Stx) and of the bacteriophages that encode the Stx genes. In E. coli, induction of the SOS response is accompanied by a higher mutation rate, called the mutator response, caused by a shift to error-prone DNA polymerases when DNA damage is too severe to be repaired by canonical DNA polymerases. Since zinc inhibited the other aspects of the SOS response, we hypothesized that zinc would also inhibit the mutator response, also known as hypermutation. We explored various different experimental paradigms to induce hypermutation triggered by the SOS response, and found that hypermutation was induced not just by classical inducers such as mitomycin C and the quinolone antibiotics, but also by antiviral drugs such as zidovudine and anti-cancer drugs such as 5-fluorouracil, 6-mercaptopurine, and azacytidine. Zinc salts inhibited the SOS response and the hypermutator phenomenon in E. coli as well as in Klebsiella pneumoniae, and was more effective in inhibiting the SOS response than other metals. We then attempted to determine the mechanism by which zinc, applied externally in the medium, inhibits hypermutation. Our results show that zinc interferes with the actions of RecA, and protects LexA from RecA-mediated cleavage, an early step in initiation of the SOS response. The SOS response may play a role in the development of antibiotic resistance and the effect of zinc suggests ways to prevent it.

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Section: Resultssupporting

confidence: 83%

Zinc blocks SOS-induced antibiotic resistance via inhibition of RecA in Escherichia coli

et al. 2017

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“…UV light comprises three broad categories based on their wavelength: UVA (320–400 nm), UVB (290–320 nm), and UVC (240–290 nm). UVC is the most harmful to living organism due to its exorbitantly high frequency and is mostly absorbed by the stratospheric ozone [10,11]. A part of UVB radiation is also absorbed in the stratosphere, though majority of UVB radiation reaches the earth’s surface, and is responsible for serious health comes, such as skin cancer by inducing DNA damage.…”

Section: Introductionmentioning

confidence: 99%

“…Although there are in vivo repair mechanisms to manage and correct DNA mutations and maintain is integrity such as photo-reactivation, base/nucleotide excision repair, DNA replication related methyl mismatch repair, in addition to large scale and nonspecific repair systems (SOS response and apoptosis), the degree of repair depends on the extent of damage and the status of the repair systems of the human body [10]. Therefore, intake of natural antioxidants and immune boosters are highly recommended for maintaining a healthy state of the DNA and eventually the whole body [4,6].…”

Section: Introductionmentioning

confidence: 99%

Genoprotective effects of Chaga mushroom (Inonotus obliquus) polysaccharides in UVB-exposed embryonic zebrafish (Danio rerio) through coordinated expression of DNA repair genes

Eid

Mohanty

Das

2020

Preprint

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BackgroundChaga mushroom (Inonotus obliquus) is one of the most promising antioxidants with incredible health-promoting effects. Chaga polysaccharides (IOP) have been reported to enhance immune response and alleviate oxidative stress during development. However, the effects of IOP on the genotoxicity in model organisms are yet to be clarified.MethodsZebrafish embryos (12 hours post fertilization, hpf) were exposed to transient UVB (12 J/m2/s, 310 nm) for 10 secs using a UV hybridisation chamber, followed by IOP treatment (2.5 mg/mL) at 24 hpf for up to 7 days post fertilization (dpf). The genotoxic effects were assessed using acridine orange staining, alkaline comet assay, and qRT-PCR for screening DNA repair genes.ResultsWe found significant reduction in DNA damage and amelioration of the deformed structures in the IOP-treated zebrafish exposed to UVB (p < 0.05) at 5 dpf and thereafter. In addition, the relative mRNA expressions of XRCC-5, XRCC-6, RAD51, P53, and GADD45 were significantly upregulated in the IOP-treated UVB-exposed zebrafish. Pathway analysis demonstrated coordinated regulation of DNA repair genes, suggesting collective response during UVB exposure.ConclusionsOverall, IOP treatment ameliorated the genotoxic effects in UVB-exposed zebrafish embryos, which eventually assisted in normal development. The study suggested the efficacy of Chaga mushroom polysaccharides in mitigating UV-induced DNA damage.

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“…SOS induction up-regulates the expression of more than 40 genes, including its own coregulator recA (Fernández De Henestrosa et al 2000). The SOS genes encode proteins whose functions include mechanisms for cell-cycle checkpoint, DNA-damage tolerance and nonmutagenic DNA repair (Janion 2008;Courcelle, Crowley, and Hanawalt 1999;Friedberg et al 2006). However, when DNA damage is persistent, the error-prone DNA translesion synthesis (TLS) takes place.…”

Section: Introductionmentioning

confidence: 99%

The antioxidant drug N-acetylcysteine abolishes SOS-mediated mutagenesis produced by fluoroquinolones in bacteria

Rodríguez‐Rojas

et al. 2018

Preprint

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Certain antibiotics, particularly fluoroquinolones, induce the mutagenic SOS response and increase the levels of intracellular reactive oxygen species (ROS), which have been correlated with antibiotic lethality. Both SOS and ROS increase mutagenesis in treated bacteria, likely resulting in the appearance of resistant mutants during antibiotic treatments. However, the relative contribution of ROS and SOS on this antibiotic-mediated mutagenesis is currently unknown. We used the antioxidant molecule N-acetylcysteine (NAC) to study the contribution of ROS on the SOS response and mutagenesis mediated by the fluoroquinolone antibiotic ciprofloxacin (CIP). We show that NAC is able to reduce intracellular ROS levels, mitigating as well the SOS response caused by treatment with subinhibitory concentrations of CIP. This effect leads to the reduction of antibiotic-induced mutagenesis to levels comparable to a translesion DNA-polymerases (TLS) deficient strain, suggesting that ROS play a major role in SOS-induced mutagenesis. Collectively, our results shed light on the mechanisms underlying antibiotic-induced mutagenesis and pave the way for the use of NAC as a safe adjuvant in antibiotic therapy to inhibit antibiotic-induced mutagenesis, hence augmenting our capacity to fight against threatening bacterial infections.

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DNA Repair and Mutagenesis

Cited by 1,090 publications

References 0 publications

Zinc blocks SOS-induced antibiotic resistance via inhibition of RecA in Escherichia coli

Zinc blocks SOS-induced antibiotic resistance via inhibition of RecA in Escherichia coli

Genoprotective effects of Chaga mushroom (Inonotus obliquus) polysaccharides in UVB-exposed embryonic zebrafish (Danio rerio) through coordinated expression of DNA repair genes

The antioxidant drug N-acetylcysteine abolishes SOS-mediated mutagenesis produced by fluoroquinolones in bacteria

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