The antiviral activity of tetrazole phosphonic acids and their analogues

Hutchinson, D. W.; Naylor, M.

doi:10.1093/nar/13.23.8519

Cited by 24 publications

(29 citation statements)

References 11 publications

(19 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Radiation-induced breaks are the result of clustered free radical-mediated sugar fragmentation (28), and therefore are likely to be randomly staggered and to have cohesive overhangs of one to several bases, along with blocked 3Ј termini (14,15,17), a one-base gap in each strand, and possible ancillary base damage in the overhangs (40). Thus, the use of partial complementarities for alignment of the overhangs during gap filling and ligation would be essential for accurate restoration of the original sequence (Fig.…”

Section: Fidelity Of Dna End Joiningmentioning

confidence: 99%

“…Radiation-induced DSBs are formed by fragmentation of deoxyribose, typically leaving in each strand a one-base gap with 5Ј-phosphate and either 3Ј-phosphate or 3Ј-phosphoglycolate (PG) termini (14,15,17). Such DSBs present to repair systems a more complex substrate than simple restriction enzyme cuts, potentially increasing the possibility of errors during rejoining.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Accurate in Vitro End Joining of a DNA Double Strand Break with Partially Cohesive 3′-Overhangs and 3′-Phosphoglycolate Termini

Chen

Inamdar

Pfeiffer

et al. 2001

Journal of Biological Chemistry

108

114

View full text Add to dashboard Cite

To examine determinants of fidelity in DNA end joining, a substrate containing a model of a staggered free radical-mediated double-strand break, with cohesive phosphoglycolate-terminated 3-overhangs and a onebase gap in each strand, was constructed. In extracts of Xenopus eggs, human lymphoblastoid cells, hamster CHO-K1 cells, and a Chinese hamster ovary (CHO) derivative lacking the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs), the predominant end joining product was that corresponding to accurate restoration of the original sequence. In extracts of the Ku-deficient CHO derivative xrs6, a shorter product, consistent with 3 3 5 resection before ligation, was formed. Similar results were seen for a substrate with 5-overhangs and recessed 3-phosphoglycolate ends. Supplementation of the xrs6 extracts with purified Ku restored accurate end joining. In Xenopus and human extracts, but not in hamster extracts, gap filling and ligation were blocked by wortmannin, consistent with a requirement for DNA-PKcs activity. The results suggest a Ku-dependent pathway, regulated by DNA-PKcs, that can accurately restore the original DNA sequence at sites of free radical-mediated double-strand breaks, by protecting DNA termini from degradation and maintaining the alignment of short partial complementarities during gap filling and ligation.

show abstract

Section: Fidelity Of Dna End Joiningmentioning

confidence: 99%

mentioning

confidence: 99%

Accurate in Vitro End Joining of a DNA Double Strand Break with Partially Cohesive 3′-Overhangs and 3′-Phosphoglycolate Termini

Chen

Inamdar

Pfeiffer

et al. 2001

Journal of Biological Chemistry

108

114

View full text Add to dashboard Cite

show abstract

“…Oxidative DNA damage is therefore ascribed to a fourth oxygen species, the hydroxyl radical (HO ⅐ ). The hydroxyl radical is powerful enough to react at diffusion-limited rates with either the base or sugar residues of DNA, leading to base modification and/or strand breakage (Reaction 4, below) (10,11). HO ⅐ can be formed when H 2 O 2 is univalently reduced by transition metals.…”

mentioning

confidence: 99%

Reduced Flavins Promote Oxidative DNA Damage in Non-respiringEscherichia coli by Delivering Electrons to Intracellular Free Iron

Woodmansee

Imlay

2002

Journal of Biological Chemistry

130

163

View full text Add to dashboard Cite

When cells are exposed to external H 2 O 2 , the H 2 O 2 rapidly diffuses inside and oxidizes ferrous iron, thereby forming hydroxyl radicals that damage DNA. Thus the process of oxidative DNA damage requires only H 2 O 2 , free iron, and an as-yet unidentified electron donor that reduces ferric iron to the ferrous state. Previous work showed that H 2 O 2 kills Escherichia coli especially rapidly when respiration is inhibited either by cyanide or by genetic defects in respiratory enzymes. In this study we established that these respiratory blocks accelerate the rate of DNA damage. The respiratory blocks did not substantially affect the amounts of intracellular free iron or H 2 O 2 , indicating that that they accelerated damage because they increased the availability of the electron donor. The goal of this work was to identify that donor. As expected, the respiratory inhibitors caused a large increase in the amount of intracellular NADH. However, NADH itself was a poor reductant of free iron in vitro. This suggests that in non-respiring cells electrons are transferred from NADH to another carrier that directly reduces the iron. Genetic manipulations of the amounts of intracellular glutathione, NADPH, ␣-ketoacids, ferredoxin, and thioredoxin indicated that none of these was the direct electron donor. However, cells were protected from cyanide-stimulated DNA damage if they lacked flavin reductase, an enzyme that transfers electrons from NADH to free FAD. The K m value of this enzyme for NADH is much higher than the usual intracellular NADH concentration, which explains why its flux increased when NADH levels rose during respiratory inhibition. Flavins that were reduced by purified flavin reductase rapidly transferred electrons to free iron and drove a DNA-damaging Fenton system in vitro. Thus the rate of oxidative DNA damage can be limited by the rate at which electron donors reduce free iron, and reduced flavins become the predominant donors in E. coli when respiration is blocked. It remains unclear whether flavins or other reductants drive Fenton chemistry in respiring cells.

show abstract

“…Unlike the oxygen species H 2 O 2 and O 2 . , hydroxyl radicals have sufficient redox potential to oxidize both sugar and base residues in DNA (3)(4)(5)(6). Left unchecked, this reactivity results in a high level of specific mutagenic lesions in the cell.…”

mentioning

confidence: 99%

The YggX Protein of Salmonella enterica Is Involved in Fe(II) Trafficking and Minimizes the DNA Damage Caused by Hydroxyl Radicals

Gralnick

Downs

2003

Journal of Biological Chemistry

View full text Add to dashboard Cite

The antiviral activity of tetrazole phosphonic acids and their analogues

Cited by 24 publications

References 11 publications

Accurate in Vitro End Joining of a DNA Double Strand Break with Partially Cohesive 3′-Overhangs and 3′-Phosphoglycolate Termini

Accurate in Vitro End Joining of a DNA Double Strand Break with Partially Cohesive 3′-Overhangs and 3′-Phosphoglycolate Termini

Reduced Flavins Promote Oxidative DNA Damage in Non-respiringEscherichia coli by Delivering Electrons to Intracellular Free Iron

The YggX Protein of Salmonella enterica Is Involved in Fe(II) Trafficking and Minimizes the DNA Damage Caused by Hydroxyl Radicals

Contact Info

Product

Resources

About