Electron transfer from protein to DNA in irradiated chromatin

Cullis, Paul M.; Jones, George D.D.; Symons, Martyn C. R.; Lea, J S

doi:10.1038/330773a0

Cited by 77 publications

(28 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The effects of the direct ionization of DNA, however, are less likely to be inhibited by the folding of the chromatin. On the contrary, there are indications that radiation energy deposited in the proteins of chromatin may be transferred to the DNA, thus compounding the DNA-damaging consequences of the direct effect of ionizing radiation [37]. Alternatively, the difference seen in "native" and compact chromatin could reflect an inability of the Fe(ll)-EDTA complex to penetrate these chromatin structures.…”

Section: Discussionmentioning

confidence: 99%

Efficient protection against oxidative DNA damage in chromatin

Ljungman

Hanawalt

1992

Molecular Carcinogenesis

123

View full text Add to dashboard Cite

The role of histones and higher order chromatin structures in protecting against oxidative DNA damage was investigated using an in vitro system consisting of nuclear and nucleoid monolayers as model chromatin substrates. These substrates, derived from human skin fibroblasts, were challenged with hydroxyl radicals produced via a Fenton reaction involving Fe(II)-ethylenediaminetetraacetic acid and ascorbic acid. The resulting DNA strand breaks were measured using the alkaline unwinding technique. The sequential removal of chromosomal proteins from the DNA by pretreating nuclear monolayers with increasing concentrations of salt dramatically increased the frequency of hydroxyl radical-induced DNA strand breaks. Furthermore, the DNA in decondensed chromatin was found to contain 14-fold fewer DNA strand breaks than naked, supercoiled DNA, whereas the DNA of "native" chromatin and "condensed" chromatin contained 100-fold and 300-fold fewer breaks, respectively. We conclude that the binding of histones to the DNA and its organization into higher order chromatin structures dramatically protects the DNA against hydroxyl radical-induced DNA strand breaks and thus should be considered part of the cellular defense against the induction of oxidative DNA damage.

show abstract

Section: Discussionmentioning

confidence: 99%

Efficient protection against oxidative DNA damage in chromatin

Ljungman

Hanawalt

1992

Molecular Carcinogenesis

123

View full text Add to dashboard Cite

show abstract

“…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: 89%

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

2009

View full text Add to dashboard Cite

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.

show abstract

“…Possible explanations are: mtDNA is located close to the ROS producing OXPHOS and mtDNA lacks protective histones [81,82]. However, there is a debate about the protective role of histones, as there is also evidence showing that the electrons can transfer easily from histones to DNA leading to damage [83] and under some conditions (exposure to Cu(II)/H 2 O 2 ) histones can even enhance DNA damage [84]. It is also suggested that DNA-binding proteins of mitochondrial nucleoids can be as equally protective as histones for mtDNA under H 2 O 2 or X-ray exposure [85,86].…”

Section: Mtdna Characteristicsmentioning

confidence: 96%

How do changes in the mtDNA and mitochondrial dysfunction influence cancer and cancer therapy? Challenges, opportunities and models

Gisbergen

Voets

Starmans

et al. 2015

Mutation Research/Reviews in Mutation Research

170

151

View full text Add to dashboard Cite

Several mutations in nuclear genes encoding for mitochondrial components have been associated with an increased cancer risk or are even causative, e.g. succinate dehydrogenase (SDHB, SDHC and SDHD genes) and iso-citrate dehydrogenase (IDH1 and IDH2 genes). Recently, studies have suggested an eminent role for mitochondrial DNA (mtDNA) mutations in the development of a wide variety of cancers. Various studies associated mtDNA abnormalities, including mutations, deletions, inversions and copy number alterations, with mitochondrial dysfunction. This might, explain the hampered cellular bioenergetics in many cancer cell types. Germline (e.g. m.10398A>G; m.6253T>C) and somatic mtDNA mutations as well as differences in mtDNA copy number seem to be associated with cancer risk. It seems that mtDNA can contribute as driver or as complementary gene mutation according to the multiple-hit model. This can enhance the mutagenic/clonogenic potential of the cell as observed for m.8993T>G or influences the metastatic potential in later stages of cancer progression. Alternatively, other mtDNA variations will be innocent passenger mutations in a tumor and therefore do not contribute to the tumorigenic or metastatic potential. In this review, we discuss how reported mtDNA variations interfere with cancer treatment and what implications this has on current successful pharmaceutical interventions. Mutations in MT-ND4 and mtDNA depletion have been reported to be involved in cisplatin resistance. Pharmaceutical impairment of OXPHOS by metformin can increase the efficiency of radiotherapy. To study mitochondrial dysfunction in cancer, different cellular models (like ρ(0) cells or cybrids), in vivo murine models (xenografts and specific mtDNA mouse models in combination with a spontaneous cancer mouse model) and small animal models (e.g. Danio rerio) could be potentially interesting to use. For future research, we foresee that unraveling mtDNA variations can contribute to personalized therapy for specific cancer types and improve the outcome of the disease.

show abstract

Electron transfer from protein to DNA in irradiated chromatin

Cited by 77 publications

References 0 publications

Efficient protection against oxidative DNA damage in chromatin

Efficient protection against oxidative DNA damage in chromatin

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

How do changes in the mtDNA and mitochondrial dysfunction influence cancer and cancer therapy? Challenges, opportunities and models

Contact Info

Product

Resources

About