Inhibitors of ribonucleotide reductase alter DNA repair in human fibroblasts through specific depletion of purine deoxynucleotide triphosphates |
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Authors: | Ronald D Snyder |
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Institution: | (1) Stauffer Chemical Company, Farmington, CT, USA;(2) Stauffer Chemical Company, 400 Farmington Avenue, 06032 Farmington, CT, USA |
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Abstract: | Hydroxyurea, deoxyadenosine, pyridine-2-carboxaldehyde thiosemicarbazone, pyrazoloimidazole, 3,5-diamino-1,2,4 triazole (guanazole), 3,4,5-trihydroxy benzohydroxamic acid and 3,4-dihydroxy benzohydroxamic acid were examined for their effects on cellular dNTP pools, DNA excision repair, DNA replication and deoxynucleoside uptake in human diploid fibroblasts. All 7 agents were effective inhibitors of the UV excision repair process in noncycling quiescent cells, but not in rapidly dividing log-phase cells. This differential effect clearly demonstrates dependency upon modulation of cellular purine dNTP pool levels at the level of the reductase. Repair synthesis is shown to be less sensitive to all 7 reductase inhibitors than is replicative synthesis. Studies on cellular uptake of labeled DNA precursors in inhibitor-treated cells support the notion that deoxynucleosides cannot channel into the replicative synthesis process whereas they are readily utilized at repairing sites.Abbreviations HU
hydroxyurea
- dA
deoxyadenosine
- TSC
pyridine-2-carboxaldehyde thiosemicarbazone
- IMPY
pyrazoloimidazole
- THBA
3,4,5-trihydroxy benzohydroxamic acid
- DHBA
3,4-dihydroxy benzohydroxamic acid
- UDS
unscheduled DNA synthesis
- dT
thymidine
- dNTP
deoxynucleoside triphosphate |
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Keywords: | DNA repair dNTPs ribonucleotide reductase inhibitors human fibroblasts |
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