The effects of thymidine on deoxyribonucleotide pool levels, cytotoxicity and mutation induction in Friend mouse erythroleukaemia cells.
The ability of excess thymidine (10(-6)-10(-3) M) to enhance the frequency of 6-thioguanine (6-TG) resistant cell mutants and 2,6-diaminopurine (DAP) resistant cell mutants in Friend mouse erythroleukaemia cells, clone 707, was investigated. A significant increase in mutant frequency for both markers was observed at the higher (10(-4) and 10(-3) M) thymidine treatments. Measurements of deoxyribonucleoside triphosphate pool sizes in the cells revealed a dramatic elevation of the deoxythymidine triphosphate and deoxyguanosine triphosphate pools, an increase in the deoxyadenosine triphosphate pool and an almost complete disappearance of the deoxycytidine triphosphate pool at the higher thymidine treatments. This complemented the mutagenesis data. These results support the view that increases in mutant frequency may take place following perturbations in DNA precursor pools through a resultant decrease in the fidelity of DNA synthesis. Measurements of deoxyribonucleoside triphosphate pools were also carried out on clone 707 Friend cells and a thymidine kinase-deficient subclone, 707 BUF. The thymidine kinase-deficient subclone had significantly reduced deoxythymidine triphosphate and deoxyguanosine triphosphate pools relative to those observed in-clone 707 cells. The previously observed mutagen hypersensitivity in thymidine kinase-deficient Friend cells may result through pool imbalance rendering DNA excision repair error prone.
Biomedical Sciences Research Centre, University of Ulster, Coleraine, Northern Ireland.
Y A
YA
Wilkinson
P G
PG
McKenna
D015075:2-Aminopurine / Q000031:analogs & derivatives; D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects*; D002999:Clone Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003854:Deoxyribonucleotides / Q000378:metabolism*; D004351:Drug Resistance / Q000235:genetics; D005622:Friend murine leukemia virus; D004915:Leukemia, Erythroblastic, Acute / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009153:Mutagens; D009154:Mutation; D013866:Thioguanine; D013936:Thymidine / Q000633:toxicity*
D003854:Deoxyribonucleotides; D009153:Mutagens; D015075:2-Aminopurine; C007300:2,6-diaminopurine; D013866:Thioguanine; D013936:Thymidine