DNA and chromosome damage induced by bleomycin in mammalian cells: An update

Bolzán, Alejandro D.; Bianchi, Martha S.

doi:10.1016/j.mrrev.2018.02.003

Cited by 60 publications

(51 citation statements)

References 107 publications

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“…Additional candidate genes encode proteins which could affect bleomycin-induced pulmonary fibrosis through their DNA damage or epithelial cell functions. In detail, bleomycin treatment can lead to DNA damage (Bolzán and Bianchi 2018 ) thus variants in Pbx2 , whose protein is DNA binding (Selleri et al 2004 ), in Stk19 encoding a nuclear locating kinase (Boeing et al 2016 ) or in Atf6b , which encodes a transcription factor (Thuerauf et al 2004 ) could create a strain-dependent response to bleomycin. There is also evidence that bleomycin damages epithelial cells in the pulmonary fibrosis process (Jin et al 2018 ), thus genetic variants influencing epithelial cell function could affect susceptibility to fibrosis.…”

Section: Discussionmentioning

confidence: 99%

Fine mapping of the major bleomycin-induced pulmonary fibrosis susceptibility locus in mice

2018

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Susceptibility to fibrotic lung disease differs among people and among inbred strains of mice exposed to bleomycin where C57BL/6J mice are susceptible and C3H/HeJ mice are spared fibrotic disease. Genetic mapping studies completed in offspring derived from these inbred strains revealed the inheritance of C57BL/6J alleles at loci, including the major locus on chromosome 17, called Blmpf1 bleomycin-induced pulmonary fibrosis 1, to be linked to pulmonary fibrosis in treated mice. In the present study, to reduce the interval of Blmpf1, we bred and phenotyped a panel of subcongenic mice with C3H/HeJ alleles in a C57BL/6J background. Subcongenic mice received bleomycin via osmotic minipump and the fibrosis phenotype was measured histologically. Inheritance of C3H/HeJ alleles from 34.31 to 35.02 Mb was revealed to spare bleomycin-induced pulmonary fibrosis of C57BL/6J mice. From database analysis, 40 protein coding genes have been mapped to this reduced Blmpf1 interval, 18 of which contain C57BL/6J:C3H/HeJ sequence polymorphisms predicted to affect protein structure or to confer allele-dependent expression, and by RT-PCR analysis of lung tissue, we show 6 of these genes to differ in expression between C57BL/6J and C3H/HeJ mice. Genes known to regulate T cell numbers and activation (Btnl family, Notch4) are among the limited list of potential causal variants leading to lung disease in this model and the bronchoalveolar lavage of protected subcongenic mice had fewer lymphocytes, post bleomycin, than did C57BL/6J mice. We conclude that Blmpf1genes contributing to the susceptibility to bleomycin-induced pulmonary fibrosis could alter the adaptive immune response of C57BL/6J mice.Electronic supplementary materialThe online version of this article (10.1007/s00335-018-9774-3) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Fine mapping of the major bleomycin-induced pulmonary fibrosis susceptibility locus in mice

2018

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“…Nucleosome cores are known to protect DNA from bleomycin cleavage [ 98 , 102 ]. DNA binding proteins, for example transcription factors, have also been observed to protect DNA from bleomycin cleavage [ 94 , 95 , 96 , 97 , 102 ]. Proteins bound to DNA can distort the structure of DNA and this can lead to an alteration in the DNA sequence specificity of bleomycin cleavage in cellular DNA compared to purified genomic DNA.…”

Section: Comparison Of the Bleomycin Genome-wide Sequence Specifimentioning

confidence: 99%

“…As mentioned above, chromatin structure affects the interaction of bleomycin with cellular DNA where nucleosome cores and other DNA binding proteins prevent bleomycin from cleaving DNA [ 102 ]. It has been demonstrated that bleomycin targets the linker region of nucleosomes rather than the core DNA and it can be used to footprint chromatin structure in human cells [ 98 , 107 , 108 ].…”

Section: Chromatin Structure Affects the Interaction Of Bleomycinmentioning

confidence: 99%

The Interaction of the Metallo-Glycopeptide Anti-Tumour Drug Bleomycin with DNA

Murray

Chen

Chung

2018

IJMS

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The cancer chemotherapeutic drug, bleomycin, is clinically used to treat several neoplasms including testicular and ovarian cancers. Bleomycin is a metallo-glycopeptide antibiotic that requires a transition metal ion, usually Fe(II), for activity. In this review, the properties of bleomycin are examined, especially the interaction of bleomycin with DNA. A Fe(II)-bleomycin complex is capable of DNA cleavage and this process is thought to be the major determinant for the cytotoxicity of bleomycin. The DNA sequence specificity of bleomycin cleavage is found to at 5′-GT* and 5′-GC* dinucleotides (where * indicates the cleaved nucleotide). Using next-generation DNA sequencing, over 200 million double-strand breaks were analysed, and an expanded bleomycin sequence specificity was found to be 5′-RTGT*AY (where R is G or A and Y is T or C) in cellular DNA and 5′-TGT*AT in purified DNA. The different environment of cellular DNA compared to purified DNA was proposed to be responsible for the difference. A number of bleomycin analogues have been examined and their interaction with DNA is also discussed. In particular, the production of bleomycin analogues via genetic manipulation of the modular non-ribosomal peptide synthetases and polyketide synthases in the bleomycin gene cluster is reviewed. The prospects for the synthesis of bleomycin analogues with increased effectiveness as cancer chemotherapeutic agents is also explored.

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“…Bleomycin (BLM), a mixture of glycopeptides isolated from Streptomyces verticillus , is an anti-neoplastic/antibiotic drug for the treatment of some forms of cancer ( 5 ). It acts through DNA fragmentation, an activity modulated by many factors in different cell types including chromatin structure and DNA repair machinery, as well as antioxidant and metabolic enzymes ( 5 ). The lack of BLM hydrolase in pulmonary epithelial cells is thought to be the main reason for the observed toxicity of BLM in the lung, resulting in the development of pulmonary fibrosis as a side effect in treated cancer patients.…”

Section: Introductionmentioning

confidence: 99%

Bleomycin Revisited: A Direct Comparison of the Intratracheal Micro-Spraying and the Oropharyngeal Aspiration Routes of Bleomycin Administration in Mice

et al. 2018

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Idiopathic Pulmonary Fibrosis (IPF) is a fatal disease characterized by exuberant deposition of extracellular matrix components, deterioration of lung architecture and impairment of lung functions. Its etiopathogenesis remains incompletely understood, as reflected in the lack of an appropriate therapy. Modeling the human disease in mice via the administration of bleomycin (BLM), despite the inherent limitations, has provided valuable insights into the underlying pathogenetic mechanisms, and has been instrumental for the development and validation of new pharmacologic interventions. Here we have directly compared the, most widely used, intratracheal (IT) route of administration with oropharyngeal aspiration (OA). Our results suggest that the OA route of BLM-administration can be used as a safe and effective alternative, minimizing peri-operative and experimental mortality, while preserving a solid fibrotic profile, as assessed with a plethora of standardized readout assays.

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DNA and chromosome damage induced by bleomycin in mammalian cells: An update

Cited by 60 publications

References 107 publications

Fine mapping of the major bleomycin-induced pulmonary fibrosis susceptibility locus in mice

Fine mapping of the major bleomycin-induced pulmonary fibrosis susceptibility locus in mice

The Interaction of the Metallo-Glycopeptide Anti-Tumour Drug Bleomycin with DNA

Bleomycin Revisited: A Direct Comparison of the Intratracheal Micro-Spraying and the Oropharyngeal Aspiration Routes of Bleomycin Administration in Mice

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