Mechanisms of bleomycin-induced DNA degradation

Stubbe, JoAnne; Kozarich, John W.

doi:10.1021/cr00081a011

Cited by 898 publications

(672 citation statements)

References 69 publications

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“…The transfer of the 2-amino group from guanine to adenine residues significantly modulates the width of the minor groove in DNA as judged from experiments with the conformation-sensitive probes DNase I and uranyl nitrate [16]. Our results reinforce the view that sequence-specific cleavage of DNA by bleomycin is the result of a direct recognition of the guanine 2-amino group coupled with indirect recognition of a suitable minor groove width [1,12,17]. Whereas the carbohydrate domain of bleomycin apparently contributes little to primary sequence recognition (digital read-out), it seems to contribute noticeably to the DNA-structure recognition (analogue read-out).…”

Section: Resultssupporting

confidence: 78%

“…The structure of bleomycin A2 (Fig. 1) --the major component of the clinical formulation --is commonly divided into three functional domains: (i) the bithiazole and sulphonium side-chain which provide a DNA-binding element [1][2][3], (ii) the pseudopeptide portion which acts as a metal chelating/oxygen activation domain [1,2] and (iii) the carbohydrate moiety which may help to complex the metal, stabilise the reactive oxygenated species [4][5][6] and facilitate penetration into cells [7]. However, the exact role of the gulose-mannose disaccharide remains uncertain.…”

Section: Introductionmentioning

confidence: 99%

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Analogue versus digital recognition of DNA by bleomycin: an effect of the carbohydrate moiety

1995

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We have sought to determine the influence of the carbohydrate moiety of the antitumour antibiotic hleomycin on the sequence-specific cleavage of DNA. Both bleomycin A2 and deglycobleomycin A2 produce different cleavage patterns with DNA in which the 2-amino group has been removed from guanine, added to adenine, or both, as well as on a designed DNA fragment containing a few defined cleavage sites. Although each drug cleaves DNA primarily at GpT and GpC sites, the cleavage at these sites is frequently found to be stronger with deglycobleomycin compared with bleomycin A 2. Conversely, in most cases the cleavage at secondary sites, in particular at ApT steps, is significantly reduced or even abolished with deglycobleomycin. The results indicate that the gulose-mannose moiety of bleomycin A2 plays a significant role in the recognition of preferred nucleotide sequences and confirm the view that both secondary structure and interaction with guanine are involved in determining sequencespecific cleavage of DNA by bleomycin.Key words." Bleomycin; DNA recognition; DNA cleavage; Sequence specificity to DNA. In addition, NMR studies suggest that the carbohydrate portion could contribute to the interaction since intermolecular NOEs between the gulose and the central thymidine in the sequence d(CGCTAGCG)2 have been detected [12]. We have explored this idea by comparing the patterns of cleavage by bleomycin A2 and deglycobleomycin A2. We report that the sugar moiety of bleomycin is not mandatory for cutting at primary GpT and GpC sites but it plays a decisive role in cutting at secondary sites, particularly ApT. Materials and methods Bleomycin A2 and deglycobleomycinA pure sample of bleomycin A z was obtained from Roger-Bellon Laboratories (Neuilly-sur-Seine, France). The gulose-mannose moiety of bleomycin A2 was specifically cleaved by HF solvolysis according to a published protocol [13]. Deglycobleomycin A2 was purified by HPLC and the integrity of the deglycosylated antibiotic was checked by [~H]NMR and HR-FAB mass spectrometry. Stock solutions were prepared in 10 mM Tris-HCl buffer containing 10 mM NaC1, pH 7.0, divided into 250-gtM aliquots and stored at -20°C.

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Section: Resultssupporting

confidence: 78%

Section: Introductionmentioning

confidence: 99%

Analogue versus digital recognition of DNA by bleomycin: an effect of the carbohydrate moiety

1995

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“…This DNA-cleaving antibiotic specifically oxidizes the 4′-position of deoxyribose in DNA (8,26) and thus does not give rise to the 2-phosphoryl-1,4-dioxobutane product of 5′-oxidation. The minor amount of adducts observed with bleomycin may have resulted from DNA oxidation by Fe +2 released from or not chelated by bleomycin.…”

Section: Discussionmentioning

confidence: 99%

Formation of 1,4-Dioxo-2-butene-Derived Adducts of 2‘-Deoxyadenosine and 2‘-Deoxycytidine in Oxidized DNA

Chen

Byrns

et al. 2006

Chem. Res. Toxicol.

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Oxidation of deoxyribose in DNA produces a variety of electrophilic residues that are capable of reacting with nucleobases to form adducts such as M 1 dG, the pyrimidopurinone adduct of dG. We now report that deoxyribose oxidation in DNA leads to the formation of oxadiazabicyclo(3.3.0) octaimine adducts of dC and dA. We previously demonstrated that these adducts arise in reactions of nucleosides and DNA with trans-1,4-dioxo-2-butene, the β-elimination product of the 2-phosphoryl-1,4-dioxobutane residue arising from 5′-oxidation of deoxyribose in DNA and with cis-1,4-dioxo-2-butene, a metabolite of furan. Treatment of DNA with enediyne antibiotics capable of oxidizing the 5′-position of deoxyribose (calicheamicin and neocarzinostatin) led to a concentration-dependent formation of oxadiazabicyclo(3.3.0)octaimine adducts of dC and dA, while the antibiotic bleomycin, which is capable of performing only 4-oxidation of deoxyribose, did not give rise to the adducts. The non-specific DNA oxidant, γ-radiation, also produced the adducts that represented ~0.1% of the 2-phosphoryl-1,4-dioxobutane residues formed during the irradiation. These results suggest that the oxadiazabicyclo(3.3.0)octaimine adducts of dC and dA could represent endogenous DNA lesions arising from oxidative stresses that also give rise to other DNA adducts.

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“…Its cytotoxicity is due to its ability to effect singleand double-strand cleavage of DNA with a number of reduced metal ions and dioxygen (3)(4)(5); Fe II displays the highest in vivo activity (6). BLM provides five nitrogen-based ligands ( Fig.…”

mentioning

confidence: 99%

Definition of the intermediates and mechanism of the anticancer drug bleomycin using nuclear resonance vibrational spectroscopy and related methods

Liu

Bell

Wong

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Bleomycin (BLM) is a glycopeptide anticancer drug capable of effecting single-and double-strand DNA cleavage. The last detectable intermediate prior to DNA cleavage is a low spin Fe III peroxy level species, termed activated bleomycin (ABLM). DNA strand scission is initiated through the abstraction of the C-4′ hydrogen atom of the deoxyribose sugar unit. Nuclear resonance vibrational spectroscopy (NRVS) aided by extended X-ray absorption fine structure spectroscopy and density functional theory (DFT) calculations are applied to define the natures of Fe III BLM and ABLM as ðBLMÞFe III ─ OH and ðBLMÞFe III ðη 1 ─OOHÞ species, respectively. The NRVS spectra of Fe III BLM and ABLM are strikingly different because in ABLM the δFe─O─O bending mode mixes with, and energetically splits, the doubly degenerate, intense O─Fe─N ax transaxial bends. DFT calculations of the reaction of ABLM with DNA, based on the species defined by the NRVS data, show that the direct H-atom abstraction by ABLM is thermodynamically favored over other proposed reaction pathways.nonheme iron | structure/reactivity T he glycopeptide antibiotic bleomycin (BLM) exhibits high intrinsic anticancer cytotoxicity, and is used in chemotherapy against head, neck, and testicular cancers as well as Hodgkin lymphoma (1, 2). Its cytotoxicity is due to its ability to effect singleand double-strand cleavage of DNA with a number of reduced metal ions and dioxygen (3-5); Fe II displays the highest in vivo activity (6). BLM provides five nitrogen-based ligands ( Fig. 1 A and B) for coordination to the metal ion based on a crystal structure of peroxy Co III BLM (7). The four equatorial ligands are an imidazole nitrogen, a deprotonated amide, a pyrimidine nitrogen, and the secondary amine of the β-aminoalanine. The axial ligand is the primary amine of the β-aminoalanine.Activated BLM (ABLM) is the final intermediate detected before DNA double-strand scission (8). ABLM is proposed to be a low spin (ls) Fe III ─OOH species (9-11), that can be formed via the reaction of Fe III BLM with O 2 and an electron or through a shunt reaction between Fe III BLM and H 2 O 2 (8, 12).A prominent issue has been whether ABLM, a nonheme iron complex, performs heme type chemistry similar to P450 and peroxidase in which heterolytic cleavage of the O─O bond results in an Fe IV species with a radical on the BLM ligand. Experiments and calculations have argued against this heterolytic mechanism and suggested a mechanism where ABLM reacts directly in H-atom abstraction from the DNA backbone sugar (10,13,14). However, a recent theoretical study has postulated that ABLM formation involves reaction of the ðBLMÞFe III ─OH 2 complex with H 2 O 2 to form a ðBLMÞFe III ─O 2 H 2 complex (15). This study found the heterolytic cleavage pathway for the ðBLMÞFe III ─ H 2 O 2 complex to be thermoneutral and therefore feasible. Because ABLM is inaccessible to vibrational characterization by resonance Raman (rR) spectroscopy due to photodecay (16), we employed nuclear resonance vibrational spectroscopy (...

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Mechanisms of bleomycin-induced DNA degradation

Cited by 898 publications

References 69 publications

Analogue versus digital recognition of DNA by bleomycin: an effect of the carbohydrate moiety

Analogue versus digital recognition of DNA by bleomycin: an effect of the carbohydrate moiety

Formation of 1,4-Dioxo-2-butene-Derived Adducts of 2‘-Deoxyadenosine and 2‘-Deoxycytidine in Oxidized DNA

Definition of the intermediates and mechanism of the anticancer drug bleomycin using nuclear resonance vibrational spectroscopy and related methods

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