Chemical Mechanism of DNA Scission by (1,10-Phenanthroline)copper. Carbonyl Oxygen of 5-Methylenefuranone Is Derived from Water

Meijler, Michaël M.; Zelenko, Ottilie; Sigman, David S.

doi:10.1021/ja962409n

Cited by 160 publications

(122 citation statements)

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“…2C). Again, that result may indicate the formation by Cu(OP) 2 of some lesions that require processing by short-patch BER.…”

Section: Resultsmentioning

confidence: 96%

“…2B); at higher doses, the survival was too low to show any clear difference. Mouse embryonic fibroblasts (MEFs) treated with Cu(OP) 2 showed sensitivity comparable to MDA-MB-231 cells, with the POLB −/− MEFs more sensitive than the POLB +/+ cells (Fig. 2C).…”

Section: Resultsmentioning

confidence: 98%

“…To test for this dependence in vivo, we compared the MDA-MB-231 lines expressing WT or K72A lyase-defective Flag-Polβ. The DNA from these cells exposed to Cu(OP) 2 and probed with either anti-Polβ or anti-Flag antibodies revealed significant DPC signals only when WT Polβ was expressed (Fig. 4A).…”

Section: Resultsmentioning

confidence: 99%

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Enzyme mechanism-based, oxidative DNA–protein cross-links formed with DNA polymerase β in vivo

Quiñones

Thapar

et al. 2015

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

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Free radical attack on the C1′ position of DNA deoxyribose generates the oxidized abasic (AP) site 2-deoxyribonolactone (dL). Upon encountering dL, AP lyase enzymes such as DNA polymerase β (Polβ) form dead-end, covalent intermediates in vitro during attempted DNA repair. However, the conditions that lead to the in vivo formation of such DNA–protein cross-links (DPC), and their impact on cellular functions, have remained unknown. We adapted an immuno-slot blot approach to detect oxidative Polβ-DPC in vivo. Treatment of mammalian cells with genotoxic oxidants that generate dL in DNA led to the formation of Polβ-DPC in vivo. In a dose-dependent fashion, Polβ-DPC were detected in MDA-MB-231 human cells treated with the antitumor drug tirapazamine (TPZ; much more Polβ-DPC under 1% O2 than under 21% O2) and even more robustly with the “chemical nuclease” 1,10-copper-ortho-phenanthroline, Cu(OP)2. Mouse embryonic fibroblasts challenged with TPZ or Cu(OP)2 also incurred Polβ-DPC. Nonoxidative agents did not generate Polβ-DPC. The cross-linking in vivo was clearly a result of the base excision DNA repair pathway: oxidative Polβ-DPC depended on the Ape1 AP endonuclease, which generates the Polβ lyase substrate, and they required the essential lysine-72 in the Polβ lyase active site. Oxidative Polβ-DPC had an unexpectedly short half-life (∼30 min) in both human and mouse cells, and their removal was dependent on the proteasome. Proteasome inhibition under Cu(OP)2 treatment was significantly more cytotoxic to cells expressing wild-type Polβ than to cells with the lyase-defective form. That observation underscores the genotoxic potential of oxidative Polβ-DPC and the biological pressure to repair them.

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“…2C). Again, that result may indicate the formation by Cu(OP) 2 of some lesions that require processing by short-patch BER.…”

Section: Resultsmentioning

confidence: 96%

Section: Resultsmentioning

confidence: 98%

See 1 more Smart Citation

Enzyme mechanism-based, oxidative DNA–protein cross-links formed with DNA polymerase β in vivo

Quiñones

Thapar

et al. 2015

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

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“…Ene-diyne drugs can also attack the C5' carbon to yield a strand break terminated by an oxidized 5'-aldehydic nucleotide, which retains the base (Dedon and Goldberg, 1992). Chemical oxidants such as Cu(II)-phenanthroline (Marshall et al, 1981;Meijler et al, 1997;Perrin et al, 1996;Pope et al, 1982;Zelenko et al, 1998) can generate C1'-derived OAS (dL and 3'-P), while H 2 O 2 in the presence of reduced iron or copper produces a range of OAS (and damaged bases) (Dizdaroglu et al, 2002). However, chemical agents often have low sequence selectivity, and their utility in studying the enzymology of BER for OAS is therefore more limited than drugs such as bleomycin.…”

Section: Formation Of Oas: Radiation Biology and Synthetic Approachesmentioning

confidence: 99%

Dynamics and diversions in base excision DNA repair of oxidized abasic lesions

Demple

DeMott

2002

Oncogene

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“…As shown in Scheme I, 2′ -deoxyribonolactone (dL), an alkaline-labile lesion that is structurally related to an abasic site, is believed to be an intermediate of the C1′ pathway. dL is relatively unstable and readily undergoes β -and δ -elimination reactions of the 3′ -and 5′ -phosphate fragments, respectively, to give rise to DNA strand cleavage and a low-molecularweight product, 5-methylene-2-furanone (5-MF) (3,5,23).…”

Section: Introductionmentioning

confidence: 99%

The Release of 5-Methylene-2-Furanone from Irradiated DNA Catalyzed by Cationic Polyamines and Divalent Metal Cations

et al. 2005

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Release of 5-methylene-2-furanone (5-MF), a characteristic marker of DNA deoxyribose oxidative damage at the C1′ position, was observed in significant quantities from X-irradiated DNA. This observation, which held for DNA irradiated either in aqueous solution or as a film, requires postirradiation treatment at 90° C in the presence of polyamines and divalent metal cations at biological pH. The 5-MF product was quantified by using reverse-phase HPLC. The radiation chemical yield of 5-MF comprised more than 30% of the yield of total unaltered base release. Polylysine, spermine and Be(II) showed the strongest catalytic effect on 5-MF release, while Zn(II), Cu(II), Ni(II), putrescine and Mg(II) were substantially less efficient. We have hypothesized that the 5-MF release from irradiated DNA occurs through catalytic decomposition of the 2′ -deoxyribonolactone (dL) precursor through two consecutive β -and δ -phosphate elimination reactions. A stepwise character of the process was indicated by the S-shaped time course of 5-MF accumulation. If dL proves to be the precursor to 5-MF formation, it would then follow that dL is a very important lesion generated in DNA by ionizing radiation.

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Chemical Mechanism of DNA Scission by (1,10-Phenanthroline)copper. Carbonyl Oxygen of 5-Methylenefuranone Is Derived from Water

Cited by 160 publications

References 17 publications

Enzyme mechanism-based, oxidative DNA–protein cross-links formed with DNA polymerase β in vivo

Enzyme mechanism-based, oxidative DNA–protein cross-links formed with DNA polymerase β in vivo

Dynamics and diversions in base excision DNA repair of oxidized abasic lesions

The Release of 5-Methylene-2-Furanone from Irradiated DNA Catalyzed by Cationic Polyamines and Divalent Metal Cations

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