The effect of bleomycin on DNA in Escherichia coli K12 cells

Yamamoto, Kazuo; Hutchinson, Franklin

doi:10.1016/0009-2797(84)90032-2

Cited by 9 publications

(3 citation statements)

References 41 publications

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“…However, when we selected for bleomycin-resistant mutants after transposon mutagenesis, we obtained only bacA mutants, suggesting either that an additional uptake system does not exist or that BacA is essential for the growth of S. meliloti on LB agar. Bleomycin has been shown to induce DNA damage in E. coli, and RecA was found to be involved in repair of this damage (18). We also found that an S. meliloti recA::Tn5-233 mutant has increased sensitivity to bleomycin compared to the parent strain (V. L. Marlow, C. Rougier, G. C. Walker, and G. P. Ferguson, unpublished data), suggesting that bleomycin can enter into S. meliloti cells and cause DNA damage.…”

Section: Vol 188 2006mentioning

confidence: 99%

“…3A). Although we termed these spontaneous mutants, since bleomycin has been shown to be a DNA-damaging agent in E. coli (18), it is also possible that some of these 38 bleomycin resistance mutants arose due to bleomycin-induced DNA damage. Interestingly, the level of bleomycin resistance in these 38 mutants did not necessarily correlate with the concentration of bleomycin used for the initial selection conditions (Fig.…”

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BacA-Mediated Bleomycin Sensitivity in Sinorhizobium meliloti Is Independent of the Unusual Lipid A Modification

et al. 2006

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Sinorhizobium meliloti bacA mutants are symbiotically defective, deoxycholate sensitive, and bleomycin resistant. We show that the bleomycin resistance phenotype is independent of the lipid A alteration and that the changes giving rise to both phenotypes are likely to be involved in the inability of bacA mutants to persist within their hosts.The BacA protein is essential for Sinorhizobium meliloti, a legume symbiont, and Brucella abortus, a phylogenetically related mammalian pathogen, to establish chronic intracellular infections in their respective hosts (9,13). Although the precise function of BacA is unknown, S. meliloti and B. abortus bacAnull mutants display a range of phenotypes during growth in complex medium, including low-level resistance to bleomycin, a glycopeptide antibiotic, and increased sensitivity to detergents compared with their respective parent strains (7, 10). The detergent sensitivity phenotype led to the discovery that BacA affects the unusual very-long-chain fatty acid (VLCFA) modifications, 27-OHC28:0, 27-OH(␤OMeC4:0)C28, and 29-OHC30:0, of the lipid A in both S. meliloti and B. abortus (5, 7). Thus, in the absence of BacA, only ϳ50% of the lipid A molecules of S. meliloti and B. abortus become modified with a VLCFA, in contrast to their respective parent strains, whose lipid A molecules all contain a VLCFA modification (5). However, recent evidence suggests that the unusual lipid A modification observed during growth of wild-type S. meliloti in complex medium is important, but not essential, for the legume symbiosis (6). Thus, since additional VLCFA modifications of the lipid A occur during the symbiosis of Rhizobium leguminosarum with peas (11), and we observed a similar increase in S. meliloti lipopolysaccharide (LPS) hydrophobicity during the alfalfa symbiosis (6), we proposed a model whereby BacA could be involved in host-induced lipid A changes. These BacA-dependent lipid A changes could be essential for the chronic infection of their eukaryotic hosts by S. meliloti and B. abortus (6).Nevertheless, there also remained a formal possibility that additional lipid A-independent changes were occurring in the S. meliloti bacA-null mutant and that one or more of these changes could also be involved in the inability of bacA mutants to persist within their hosts. For example, it seemed unlikely that a reduction in the lipid A VLCFA content could account for the low-level bleomycin resistance phenotype of the S. meliloti bacA-null mutant, since deletion of the bacA homolog, sbmA, in Escherichia coli also gives rise to a similar phenotype (10), despite the fact that the lipid A of E. coli lacks VLCFA modifications (15). Thus, these data suggested that BacA might have additional effects on S. meliloti, resulting in increased sensitization of wild-type S. meliloti toward bleomycin relative to the S. meliloti bacA mutant.S. meliloti mutants completely lacking the lipid A VLCFA modification have increased sensitivity to bleomycin. Our recent discovery that the lipid A species produced by the S. m...

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Section: Vol 188 2006mentioning

confidence: 99%

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confidence: 99%

BacA-Mediated Bleomycin Sensitivity in Sinorhizobium meliloti Is Independent of the Unusual Lipid A Modification

et al. 2006

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“…In order to more fully understand the mechanism of BLM toxicity in Escherichia coli , previous studies [7], [8] have shown an increased BLM sensitivity of lexA and recA mutant strains indicating that the SOS response is an important mechanism cells use to resist the toxic effects of the drug. The increased sensitivity of recA and recBC mutant strains to BLM indicates a role for homologous recombination in cell survival [8], [9].…”

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Bleomycin Sensitivity in Escherichia coli is Medium-Dependent

Xu¹,

Brown²,

Marinus

2012

PLoS ONE

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Bleomycin (BLM) is a glycopeptide antibiotic and anti-tumor agent that targets primarily the furanose rings of DNA and in the presence of ferrous ions produces oxidative damage and DNA strand breaks. Escherichia coli cells growing in broth medium and exposed to low concentrations of BLM contain double-strand breaks and require homologous recombination to survive. To a lesser extent, the cells also require the abasic (AP) endonucleases associated with base excision repair, presumably to repair oxidative damage. As expected, there is strong induction of the SOS system in treated cells. In contrast, E. coli cells growing in glucose or glycerol minimal medium are resistant to the lethal action of BLM and do not require either homologous recombination functions or AP-endonucleases for survival. DNA ligase activity, however, is needed for cells growing in minimal medium to resist the lethal effects of BLM. There is weak SOS induction in such treated cells.

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Mechanisms of bleomycin-induced lung damage

1991

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Bleomycins are a family of compounds produced by Streptomyces verticillis. They have potent tumour killing properties which have given them an important place in cancer chemotherapy. They cause little marrow suppression, but pulmonary toxicity is a major adverse effect. The mechanisms of cell toxicity are well described based on in vitro experiments on DNA. The bleomycin molecule has two main structural components: a bithiazole component which partially intercalates into the DNA helix, parting the strands, as well as pyrimidine and imidazole structures, which bind iron and oxygen forming an activated complex capable of releasing damaging oxidants in close proximity to the polynucleotide chains of DNA. This may lead to chain scission or structural modifications leading to release of free bases or their propenal derivatives. The mechanisms are well described based on in vitro experiments on DNA, but how they relate to intact cells in whole animals is more tenuous. Bleomycin is able to cause cell damage independent from its effect on DNA by induction lipid peroxidation. This may be particularly important in the lung and in part account for its ability to cause alveolar cell damage and subsequent pulmonary inflammation. The lung injury seen following bleomycin comprises an interstitial oedema with an influx of inflammatory and immune cells. This may lead to the development of pulmonary fibrosis, characterized by enhanced production and deposition of collagen and other matrix components. Several polypeptide mediators capable of stimulating fibroblasts replication or excessive collagen deposition have been implicated in this, but the precise role of these in bleomycin-induced fibrosis is yet to be demonstrated. Current therapy for bleomycin-induced lung damage is inadequate, with corticosteroids most often used. Given the mechanism of action described above, antioxidants and iron chelators might be beneficial. Although, studies to date are equivocal and there is insufficient evidence to promote their use clinically. Novel drugs are currently being developed and it is hoped these may be more useful.

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The effect of bleomycin on DNA in Escherichia coli K12 cells

Cited by 9 publications

References 41 publications

BacA-Mediated Bleomycin Sensitivity in Sinorhizobium meliloti Is Independent of the Unusual Lipid A Modification

BacA-Mediated Bleomycin Sensitivity in Sinorhizobium meliloti Is Independent of the Unusual Lipid A Modification

Bleomycin Sensitivity in Escherichia coli is Medium-Dependent

Mechanisms of bleomycin-induced lung damage

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