Excess Electron Transport Through DNA: A Single Electron Repairs More than One UV‐Induced Lesion

Giese, Bernd; Carl, Barbara; Carl, Thomas; Carell, Thomas; Behrens, Christoph; Hennecke, Ulrich; Schiemann, Olav; Feresin, Emiliano

doi:10.1002/anie.200353264

Cited by 74 publications

(56 citation statements)

References 27 publications

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“…Such an "overhopping" of the electron acceptor is indeed observed in DNA duplexes containing two CPD lesions. [29] The problem associated with these data is that irreversible electron traps were used, which are characterized by two important parameters. First, the reduction potential of the acceptor determines how quickly it is reduced by an excess electron in the duplex.…”

Section: Introductionmentioning

confidence: 99%

Investigation of Excess‐Electron Transfer in DNA Double‐Duplex Systems Allows Estimation of Absolute Excess‐Electron Transfer and CPD Cleavage Rates

Fazio

Trindler

Heil

et al. 2010

Chemistry A European J

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To investigate the parameters and rates that determine excess-electron transfer processes in DNA duplexes, we developed a DNA double-duplex system containing a reduced and deprotonated flavin donor at the junction of two duplexes with either the same or different electron acceptors in the individual duplex substructures. This model system allows us to bring the two electron acceptors in the duplex substructures into direct competition for injected electrons and this enables us to decipher how the kind of acceptor influences the transfer data. Measurements with the electron acceptors 8-bromo-dA (BrdA), 8-bromo-dG (BrdG), 5-bromo-dU (BrdU), and a cyclobutane pyrimidine dimer, which is a UV-induced DNA lesion, allowed us to obtain directly the maximum overall reaction rates of these acceptors and especially of the T=T dimer with the injected electrons in the duplex. In line with previous observations, we detected that the overall dimer cleavage rate is about one order of magnitude slower than the debromination of BrdU. Furthermore, we present a more detailed explanation of why sequence dependence cannot be observed when a T=T dimer is used as the acceptor and we estimate the absolute excess-electron hopping rates.

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Section: Introductionmentioning

confidence: 99%

Investigation of Excess‐Electron Transfer in DNA Double‐Duplex Systems Allows Estimation of Absolute Excess‐Electron Transfer and CPD Cleavage Rates

Fazio

Trindler

Heil

et al. 2010

Chemistry A European J

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“…Chemically well defined assemblies, consisting of DNA duplexes with covalently bound oxidants, have been particularly useful in establishing the sensitivity of DNA CT to base-stacking perturbation (11)(12)(13)(14)(15)(16). Recently, analogous studies probing long-range reductive chemistry on DNA has been probed both in solution (17)(18)(19)(20) and on DNAmodified surfaces (14,15,21). As with oxidation chemistry, these reactions show only small variations in rate with distance but are remarkably sensitive to perturbations in the intervening base pair stack.…”

mentioning

confidence: 99%

Protein–DNA charge transport: Redox activation of a DNA repair protein by guanine radical

Yavin

Boal²,

Stemp

et al. 2005

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

118

124

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DNA charge transport (CT) chemistry provides a route to carry out oxidative DNA damage from a distance in a reaction that is sensitive to DNA mismatches and lesions. Here, DNA-mediated CT also leads to oxidation of a DNA-bound base excision repair enzyme, MutY. DNA-bound Ru(III), generated through a flash͞ quench technique, is found to promote oxidation of the 1؉ clusters. In ruthenium-tethered DNA assemblies, oxidative damage to the 5-G of a 5-GG-3 doublet is generated from a distance but this irreversible damage is inhibited by MutY and instead EPR experiments reveal cluster oxidation. With rutheniumtethered assemblies containing duplex versus single-stranded regions, MutY oxidation is found to be mediated by the DNA duplex, with guanine radical as an intermediate oxidant; guanine radical formation facilitates MutY oxidation. A model is proposed for the redox activation of DNA repair proteins through DNA CT, with guanine radicals, the first product under oxidative stress, in oxidizing the DNA-bound repair proteins, providing the signal to stimulate DNA repair.electron transfer ͉ iron-sulfur cluster ͉ oxidative DNA damage D NA-mediated charge transport (CT) from a distance to generate oxidative damage was first demonstrated in an assembly containing a tethered metallointercalator (1). In this assembly, photoinduced oxidative damage of the 5Ј-G of 5Ј-GG-3Ј sites was observed; this damage pattern has since become the hallmark of DNA CT chemistry, and long-range oxidative damage has been confirmed by using a variety of pendant oxidants (2-6). Long-range oxidative DNA damage has been demonstrated over a distance of at least 200 Å (7, 8). Indeed, DNA either packaged in nucleosome core particles (9) or inside the cell nucleus (10) has been found to be susceptible to long-range oxidative damage. Chemically well defined assemblies, consisting of DNA duplexes with covalently bound oxidants, have been particularly useful in establishing the sensitivity of DNA CT to base-stacking perturbation (11-16). Recently, analogous studies probing long-range reductive chemistry on DNA has been probed both in solution (17-20) and on DNAmodified surfaces (14,15,21). As with oxidation chemistry, these reactions show only small variations in rate with distance but are remarkably sensitive to perturbations in the intervening base pair stack. Mechanistic descriptions for DNA CT focused first on a mixture of hopping and tunneling. A phonon-assisted polaron model has also been put forth (22). Studies as a function of temperature have shown the CT process to be gated by base pair dynamics; in fact, base pair motions are required for CT (23, 24).We have therefore described DNA CT in the context of transport among delocalized DNA domains formed and dissolved based on sequence-dependent DNA dynamics.Given the exquisite sensitivity of DNA CT to DNA lesions and mismatches, we have recently explored a possible role for DNA CT in repair. We demonstrated that redox activity required DNA binding for MutY (25), a base excision repair (BER) enzyme fr...

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“…CT through DNA is inhibited by intervening DNA mismatches and bulges as well as by DNA-binding proteins that interfere with base pair stacking (8)(9)(10)(11)(12). Recently, studies probing long-range reductive chemistry on DNA also have been investigated both in solution (13)(14)(15) and on DNA-modified surfaces (12,16). As with oxidation chemistry, these reactions show only small variations in rate with distance but are sensitive to perturbations in the intervening base pair stack.…”

mentioning

confidence: 99%

Electron trap for DNA-bound repair enzymes: A strategy for DNA-mediated signaling

Yavin

Stemp

O’Shea

et al. 2006

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

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Despite a low copy number within the cell, base excision repair (BER) enzymes readily detect DNA base lesions and mismatches. These enzymes also contain [Fe 4S4] clusters, yet a redox role for these iron cofactors had been unclear. Here, we provide evidence that BER proteins may use DNA-mediated redox chemistry as part of a signaling mechanism to detect base lesions. By using chemically modified bases, we show electron trapping on DNA in solution with bound BER enzymes by electron paramagnetic resonance (EPR) spectroscopy. We demonstrate electron transfer from two BER proteins, Endonuclease III (EndoIII) and MutY, to modified bases in DNA containing oxidized nitroxyl radical EPR probes. Electron trapping requires that the modified base is coupled to the DNA -stack, and trapping efficiency is increased when a noncleavable MutY substrate analogue is located distally to the trap. These results are consistent with DNA binding leading to the activation of the repair proteins toward oxidation. Significantly, these results support a mechanism for DNA repair that involves DNA-mediated charge transport.base excision repair ͉ DNA charge transport ͉ iron sulfur clusters O ur laboratory has carried out a range of studies to probe and apply DNA-mediated charge transport (CT) chemistry (1). Oxidative damage to DNA from a distance through DNA CT was first demonstrated in an assembly containing a tethered metallointercalator (2). Since that time, photoinduced oxidative damage of the 5Ј-G of 5Ј-GG-3Ј sites from a distance has been observed in assemblies using various pendant oxidants (3-5). Indeed, long-range oxidative DNA damage has been demonstrated over a distance of at least 200 Å (6, 7). Besides the shallow distance dependence in reactions by DNA CT, another characteristic of this chemistry has been its exquisite sensitivity to perturbations in base pair structure. CT through DNA is inhibited by intervening DNA mismatches and bulges as well as by DNA-binding proteins that interfere with base pair stacking (8)(9)(10)(11)(12). Recently, studies probing long-range reductive chemistry on DNA also have been investigated both in solution (13-15) and on DNA-modified surfaces (12, 16). As with oxidation chemistry, these reactions show only small variations in rate with distance but are sensitive to perturbations in the intervening base pair stack.Given the unique characteristics of DNA CT chemistry, we are interested in whether DNA CT might be important physiologically. Based on the exquisite sensitivity of DNA CT to base pair lesions and mismatches, we considered in particular that DNA CT might be advantageous with respect to DNA repair. Base excision repair (BER) enzymes are exceedingly efficient in detecting DNA base lesions and mismatches, yet an understanding of that process has been elusive (17 2ϩ clusters are well separated from the enzyme active site and do not appear to participate in the glycoslyase reaction, yet they are essential for overall repair activity. Crystal structures in the absence and presence of DNA, moreov...

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Excess Electron Transport Through DNA: A Single Electron Repairs More than One UV‐Induced Lesion

Cited by 74 publications

References 27 publications

Investigation of Excess‐Electron Transfer in DNA Double‐Duplex Systems Allows Estimation of Absolute Excess‐Electron Transfer and CPD Cleavage Rates

Investigation of Excess‐Electron Transfer in DNA Double‐Duplex Systems Allows Estimation of Absolute Excess‐Electron Transfer and CPD Cleavage Rates

Protein–DNA charge transport: Redox activation of a DNA repair protein by guanine radical

Electron trap for DNA-bound repair enzymes: A strategy for DNA-mediated signaling

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