The DNA cleavage mechanism of iron-bleomycin. Kinetic resolution of strand scission from base propenal release.

Burger, Richard M.; Projan, S J; Horwitz, Susan Band; Peisach, Jack

doi:10.1016/s0021-9258(18)66659-1

Cited by 83 publications

(45 citation statements)

References 21 publications

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“…The reaction mixtures in lanes 2-6 were treated with 1 M piperidine at 95 °C for 15 min prior to electrophoresis, (b) Histograms showing oxygen dependence upon the Fe-BLMmediated ds-cleavage product in [i-32P]GT-l. Phosphorlmagergenerated histograms for the reactions shown in lanes 4 (-O2) and 5 (+O2) in panel a were normalized upon the peak corresponding to ss-cleavage occurring at T38. tion of the individual nucleotides is equivalent to that proposed for ss-cleavage induced by Fe-BLM (Burger et al, 1986;McGall et al, 1992;Rabow et al, 1990;Murugeson et al, 1985;Sugiyama et al, 1985).…”

Section: Discussionmentioning

confidence: 52%

“…The results are also consistent with an alternative mechanism for ds-cleavage described by Keller and Oppenheimer (1987) in which oxygen-dependent degradation produces an immediate strand break, thereby potentiating the binding of a second molecule of "activated BLM". Their original proposal assumed that the negatively charged products of ss-cleavage enhanced the binding of the second FeBLM, inconsistent with the kinetics of strand scission previously reported (Burger et al, 1986).…”

Section: Discussionmentioning

confidence: 81%

“…A variation of their proposal, however, might employ a negatively charged intermediate in the production of the ssbreak to enhance binding of a second FeBLM (Burger et al, 1986;McGall et al, 1992). While this model still cannot be fully discounted, results of Absalon et al (1995), examining the ratio of ss-to ds-cleavage as a function of BLM concentration and the inability of Co-BLM to significantly perturb this ratio, in conjunction with earlier studies (Povirk, 1983;Povirk et al, 1977), allow us to favor a mechanism in which one molecule of Fe-BLM is responsible for both strand breaks.…”

Section: Discussionmentioning

confidence: 99%

“…The essential factor establishing the ratio of ss-to ds-cleavage at a specific site may be related to the efficiency by which Fe-BLM can be reactivated and/or repositioned at a second site for cleavage.Studies evaluating the extent of single-strand (ss)1 and double-strand (ds) DNA cleavage mediated by bleomycin (BLM) necessitate the consideration of a mechanism for dscleavage in which a single molecule of BLM is responsible for both strand breaks (Absalon et al, 1995;Povirk et al, 1977). Incubation of BLM with Fe2+ and O2 yields a mixture of ferric-BLM and "activated BLM", a species recently shown by electrospray mass spectrometry to be BLMferric-peroxide which is kinetically competent to cause both ss-and ds-cleavage (Burger et al, 1981(Burger et al, , 1986Sam et al, 1994). However, in contrast to the enediyne family of antibiotics which are proposed to cause ds-breaks via a diradical form of the drug (Dedon and Goldberg, 1992), "activated BLM" possesses only a single reactive moiety.…”

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confidence: 99%

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Sequence-Specific Double-Strand Cleavage of DNA by Fe-Bleomycin. 2. Mechanism and Dynamics

Absalon

Wu²,

Kozarich³

et al. 1995

Biochemistry

113

133

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The mechanism of iron-bleomycin-mediated ds-cleavage of DNA has been investigated at specific sites within specific sequences using hairpin oligonucleotides (Absalon et al., 1995) and our recently developed technique for determining sequence-specific isotope effects upon oxidative degradation of DNA (Kozarich et al., 1989; Worth et al., 1993). Isotope effects upon ds-cleavage have been observed when the C-4' hydrogen of either nucleotide involved in the ds-break was substituted with deuterium. The values of the isotope effects determined for ss and ds events occurring at the same site were indistinguishable at four sites examined in detail. The results are consistent with a mechanism of ds-cleavage in which the pathways leading to ss- and ds-cleavage partition from a common intermediate subsequent to abstraction of the C-4' hydrogen from the first nucleotide involved in the cleavage. Deuterium substitution at the primary cleavage site of a ds-break failed to result in an equivalent effect on the amount of cleavage at the secondary cleavage site, suggesting that ds-cleavage may be initiated from either of the nucleotides involved in the ds-cleavage event. A kinetic preference for cleavage initiated at the 1 degree site, however, is probable. The requirement in the ds-cleavage process for O2, in addition to that needed to form "activated BLM", has been clearly demonstrated by the absence of ds-cleavage products in reactions performed under anaerobic conditions in which ss-cleavage still occurs. These results support, in part, the basic model for ds-cleavage proposed by Steighner and Povirk [(1990) Proc. Natl. Acad. Sci. U.S.A. 87, 8350-8354], in which a single molecule of BLM effects ds-cleavage and requires reactivation to effect cleavage at the second strand. The essential factor establishing the ratio of ss- to ds-cleavage at a specific site may be related to the efficiency by which Fe-BLM can be reactivated and/or repositioned at a second site for cleavage.

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Section: Discussionmentioning

confidence: 52%

Section: Discussionmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Sequence-Specific Double-Strand Cleavage of DNA by Fe-Bleomycin. 2. Mechanism and Dynamics

Absalon

Wu²,

Kozarich³

et al. 1995

Biochemistry

113

133

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“…Since the redox potential for Fe III /Fe II is beyond the biological window, the complexes are unlikely to get reduced in the presence of cellular thiols thus eliminating any possibility of their chemical nuclease activity [38] . This is expected to reduce any dark cytotoxicity in the cell proliferation assays.…”

Section: Resultsmentioning

confidence: 99%

Biotin‐Appended Iron(III) Complexes of Curcumin for Targeted Photo‐Chemotherapy

et al. 2021

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Iron(III) complexes of curcumin (Hcur) having a tridentate NNN‐donor dipicolylamine‐based ligand L1 and its biotinylated analogue L2, namely, [Fe(L1)(cur)Cl] (1) and [Fe(L2)(cur)Cl] (2), were prepared, characterized and their photo‐induced cytotoxicity studied. The complexes exhibited curcumin‐based absorption band near 430 nm and emission maxima at 520 nm. Complex 2 with a biotin moiety showed enhanced cellular uptake and higher cytotoxicity compared to its non‐biotin analogue 1. The visible light induced cytotoxicity was studied in HeLa, MCF‐7 and HepG2 cell lines. Complex 2 displayed photodynamic effect (400–700 nm, 10 J cm−2) giving an IC50 value of ∼4 μM in HeLa and MCF‐7 cells, while being significantly non‐toxic in the dark (IC50>100 μM). A 5‐fold increase in cytotoxicity was observed in HepG2 cells (IC50∼0.7 μM) for the biotin‐appended complex 2. In vitro generation of reactive oxygen species (ROS) was observed from dichlorofluorescein diacetate (DCFDA) assay. The mode of cell death was apoptotic. Formation of hydroxyl radicals as the ROS was evidenced from the plasmid pUC19 DNA photo‐cleavage studies. The complexes demonstrated the ability to act as targeted PDT (photodynamic therapy) drugs.

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Bleomycin

Moore¹

2002

Encyclopedia of Molecular Biology

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The DNA cleavage mechanism of iron-bleomycin. Kinetic resolution of strand scission from base propenal release.

Cited by 83 publications

References 21 publications

Sequence-Specific Double-Strand Cleavage of DNA by Fe-Bleomycin. 2. Mechanism and Dynamics

Sequence-Specific Double-Strand Cleavage of DNA by Fe-Bleomycin. 2. Mechanism and Dynamics

Biotin‐Appended Iron(III) Complexes of Curcumin for Targeted Photo‐Chemotherapy

Bleomycin

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