Thymidine in the micromolar range promotes rejoining of UVC-induced DNA strand breaks and prevents azidothymidine from inhibiting the rejoining in quiescent human lymphocytes.
The effect and inter-individual variation in the effect of exogenously added deoxynucleosides (2 x 10(-6) M) on rejoining of UVC-induced DNA strand breaks was examined in quiescent human lymphocytes from 25 healthy persons. Thymidine at concentrations below 2 x 10(-6) M, effectively and with statistically extreme significance, increased rejoining of UVC-induced DNA strand breaks in the lymphocytes of every one of the 25 persons tested (p < 0.0001, Wilcoxon's signed ranks test). The mean stimulation after 20 h of postirradiation repair was 48% (range 18-78%) with an inter-individual variation of 30% (coefficient of variation, CV). Deoxyguanosine stimulated rejoining in 16, but inhibited in three of 19 test persons (mean stimulation 28%, range -31 to 71%). The stimulating effect of deoxyguanosine was also extremely significant (p < 0.0004). Deoxycytidine and deoxyadenosine stimulated rejoining in some persons and inhibited it in others, and without statistical significance (p values above 0.5). The stimulating effect of thymidine was significantly inhibited by deoxycytidine (p < 0.05, n = 12) whereas deoxyguanosine neither promoted or inhibited the stimulation by thymidine (p = 1, n = 12). Rejoining of DNA strand breaks induced by methyl methanesulfonate did not appear significantly stimulated or inhibited by any of the four deoxynucleosides. Finally, the inhibiting effect of azidothymidine (AZT) on rejoining of UVC-induced DNA strand breaks was nullified by the addition of thymidine. In three donors examined, 10(-4) M AZT inhibited the rejoining by about 40-50%. The presence of less than 10(-5) M thymidine reduced the level of UVC-induced DNA strand breaks to below the level in control lymphocytes allowed to repair without AZT. These results indicate that among the four deoxynucleoside triphosphates, dTTP has a crucial role on the repair of UVC-induced DNA damage in quiescent lymphocytes. The results also indicate that an expansion of the dTTP pool may counteract the inhibiting effect of AZT on DNA repair in quiescent lymphocytes.
Munch-Petersen
B
B
Department of Life Sciences and Chemistry, Roskilde University, Denmark. bmp@virgil.ruc.dk
D000328:Adult; D004249:DNA Damage / Q000187:drug effects / Q000528:radiation effects; D004260:DNA Repair; D003839:Deoxyadenosines / Q000494:pharmacology; D003841:Deoxycytidine / Q000494:pharmacology; D003849:Deoxyguanosine / Q000494:pharmacology; D006801:Humans; D008214:Lymphocytes; D008741:Methyl Methanesulfonate / Q000494:pharmacology; D008875:Middle Aged; D015203:Reproducibility of Results; D013936:Thymidine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D014466:Ultraviolet Rays / Q000009:adverse effects; D015215:Zidovudine / Q000037:antagonists & inhibitors*
D003839:Deoxyadenosines; D003841:Deoxycytidine; D015215:Zidovudine; D008741:Methyl Methanesulfonate; D003849:Deoxyguanosine; D013936:Thymidine