DNA-Bound Peptide Radicals Generated through DNA-Mediated Electron Transport

Wagenknecht, Hans‐Achim; Stemp, Eric D. A.; Barton, Jacqueline K.

doi:10.1021/bi992897m

Cited by 55 publications

(66 citation statements)

References 58 publications

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“…35 In this context, amino acids having oxidation potentials less than that of guanine (1.29 V at pH 7) that can transfer one electron to guanine in a favorable manner are of paramount importance. 35,36 The occurrence of such reactions has already been observed by the flash-quench technique, 37 ESR, 38 pulse radiolysis, 39 and other experimental 36,40,41 studies.…”

Section: Introductionmentioning

confidence: 81%

Protection Against Radiation-Induced DNA Damage by Amino Acids: A DFT Study

2009

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Direct and indirect radiation-induced DNA damage is associated with the formation of radical cations (G(+)) and radical anions (G(-)) of guanine, respectively. Deprotonation of G(+) and dehydrogenation of G(-) generate guanine neutral radical [G(-H)] and guanine anion [G(-H)(-)], respectively. These products are of worrisome concern, as they are involved in reactions that are related to certain lethal diseases. It has been observed that guanyl radicals can be repaired by amino acids having strong reducing properties that are believed to be the residues of DNA-bound proteins such as histones. As a result, repair of G(-H) and G(-H)(-) by the amino acids cysteine and tyrosine has been studied here in detail by density functional theory in both the gas phase and aqueous medium using the polarized continuum and Onsager solvation models of self-consistent reaction field theory. Solvation in aqueous medium using three explicit water molecules was also studied. Four equivalent tautomers of each the above radical and anion that will be formed through proton and hydrogen loss from all of the nitrogen centers of guanine radical cation and guanine radical anion, respectively, were considered in the present study. It was found that in both the gas phase and aqueous medium, normal guanine can be retrieved from its radical-damaged form by a hydrogen-atom-transfer (HT) mechanism. Normal guanine can also be retrieved from its anionic damaged form in both the gas phase and aqueous medium through a two-electron-coupled proton-transfer (TECPT) mechanism or a one-step hydrogen-atom- and electron-transfer (OSHET) mechanism. The present results are discussed in light of the experimental findings.

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Section: Introductionmentioning

confidence: 81%

Protection Against Radiation-Induced DNA Damage by Amino Acids: A DFT Study

2009

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“…Guanine radicals generated with a ruthenium photooxidant can be transferred to aromatic amino acid side chains (tyrosine and tryptophan) present in positively charged peptides (Lys-Tyr-Lys and Lys-Trp-Lys) [34]. Photolyase, an enzyme that uses CT to repair thymine dimer lesions in DNA, contains a flavin cofactor that can also be oxidized and reduced via the DNA π-stack when probed electrochemically on DNAmodified electrodes [35].…”

Section: Oxidation From a Distance Of Dna-bound Proteinsmentioning

confidence: 99%

Biological contexts for DNA charge transport chemistry

Merino

Boal

Barton

2008

Current Opinion in Chemical Biology

114

105

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SUMMARYMany experiments have now shown that double helical DNA can serve as a conduit for efficient charge transport (CT) reactions over long distances in vitro. These results prompt the consideration of biological roles for DNA-mediated CT. DNA CT has been demonstrated to occur in biologically relevant environments such as within the mitochondria and nuclei of HeLa cells as well as in isolated nucleosomes. In mitochondria, DNA damage that results from CT is funneled to a critical regulatory element. Thus DNA CT provides a strategy to funnel damage to particular sites in the genome. DNA CT might also be important in long range signaling to DNA-bound proteins. Both DNA repair proteins, containing Fe-S clusters, and the transcription factor, p53, which is regulated through thiol-disulfide switches, can be oxidized from a distance through DNA-mediated CT. These observations highlight a means through which oxidative stress may be chemically signaled in the genome over long distances through CT from guanine radicals to DNAbound proteins. Moreover, DNA-mediated CT may also play a role in signaling among DNAbinding proteins, as has been proposed as a mechanism for how DNA repair glycosylases more efficiently detect lesions inside the cell.

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“…10 Photo-induced one-electron oxidation of guanine by electronically-excited state of Ru-complex covalently-linked to DNA initiates formation of the cross-links with lysine-tyrosine-lysine tripeptide. 12, 13 …”

Section: Resultsmentioning

confidence: 99%

Generation of guanine–amino acid cross-links by a free radical combination mechanism

Uvaydov

Geacintov

Shafirovich

2014

Phys. Chem. Chem. Phys.

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A direct method has been developed for the in vitro synthesis of stable DNA – protein cross-links (DPC’s) between guanine and amino acids (lysine, arginine). This method employs the combination of guanine neutral radicals, G(-H)•, and side-chain C-centered amino acid radicals. The latter were generated indirectly after first causing the selective photoionization of 2-aminopurine (2AP) embedded in the oligonucleotide, 5’-d(CC[2AP]TCGCTACC) by intense nanosecond 308 nm excimer laser pulses. The 2AP radical cation deprotonates rapidly to form the 2AP(-H)• neutral radical which, in turn, oxidizes the nearby guanine to form the neutral guanine G(-H)• radical, as described previously (Shafirovich et al. J. Phys. Chem. B, 2001, 105, 8431). In parallel, the hydrated electrons generated by the photoionization of 2AP, are scavenged by nitrous oxide to generate hydroxyl radicals. In the presence of a large excess of the amino acids, the hydroxyl radicals oxidize the latter to produce C-centered amino acid radicals that combine with the G(-H)• radicals to form the guanine-amino acid cross-linked oligonucleotide product. Analogous products were generated by photoionizing the free nucleoside, 2’,3’,5’-tri-O-acetylguanoise, (tri-O-Ac-Guo) using intense nanosecond 266 nm Nd: Yag laser pulse irradiation. The guanine – amino acid cross-links thus produced either site-specifically positioned in oligonucleotides, or in the free nucleoside tri-O-Ac-Guo were isolated by HPLC methods and identified by high resolution LC-TOF/MS and LC-MS/MS methods. The possibility is discussed that analogous guanine-amino acid cross-linked products could be formed in vivo under single hit radical generation mechanisms during oxidative stress.

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DNA-Bound Peptide Radicals Generated through DNA-Mediated Electron Transport

Cited by 55 publications

References 58 publications

Protection Against Radiation-Induced DNA Damage by Amino Acids: A DFT Study

Protection Against Radiation-Induced DNA Damage by Amino Acids: A DFT Study

Biological contexts for DNA charge transport chemistry

Generation of guanine–amino acid cross-links by a free radical combination mechanism

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