The role of deoxynucleoside triphosphate pools in the inhibition of DNA-excision repair and replication in human cells by hydroxyurea.
The effects of hydroxyurea (HU) on the DNA-excision repair process in human cells has been systematically examined. It is demonstrated that HU induces DNA single-strand break accumulation in a dose-dependent fashion in ultraviolet-irradiated and MMS-treated confluent but not log-phase fibroblasts and that these breaks are clearly the consequence of the inhibition by HU of the enzyme, ribonucleotide reductase. The breaks form rapidly, are stable for at least 10 h and largely disappear by 20 h. The production of these DNA-strand breaks is antagonized by a combined treatment of 10 microM deoxyadenosine, deoxycytidine and deoxyguanosine whereas thymidine potentiates strand-break formation at low HU concentrations. It is also confirmed that HU, while inhibiting replicative synthesis has no apparent inhibitory effect on unscheduled DNA synthesis (UDS) although the increased uptake of labeled DNA precursors into HU-treated cells makes it difficult to assess the actual effects on the repair-synthetic process. Analysis of the effects of HU on deoxynucleoside triphosphate pool levels and the demonstration of the failure of the HU block to replicative synthesis to be reversed by high (1 mM) concentrations of added deoxynucleosides lend support to the notion of compartmentalized dNTP pools for repair and replication.
D002478:Cells, Cultured; D004260:DNA Repair / Q000187:drug effects* / Q000528:radiation effects; D004261:DNA Replication / Q000187:drug effects* / Q000528:radiation effects; D003854:Deoxyribonucleotides / Q000378:metabolism*; D006801:Humans; D006918:Hydroxyurea / Q000633:toxicity*; D007700:Kinetics; D008741:Methyl Methanesulfonate / Q000633:toxicity; D012867:Skin / Q000187:drug effects / Q000528:radiation effects; D012879:Skin Physiological Phenomena; D014466:Ultraviolet Rays
D003854:Deoxyribonucleotides; D008741:Methyl Methanesulfonate; D006918:Hydroxyurea