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 hea lthy persons. Thymidine at concentrations below 2 x 10(-6) M, effectiv ely and with statistically extreme significance, increased rejoining o f 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 mea n stimulation after 20 h of postirradiation repair was 48% (range 18-7 8%) with an inter-individual variation of 30% (coefficient of variatio n, CV). Deoxyguanosine stimulated rejoining in 16, but inhibited in th ree of 19 test persons (mean stimulation 28%, range -31 to 71%). The s timulating effect of deoxyguanosine was also extremely significant (p < 0.0004). Deoxycytidine and deoxyadenosine stimulated rejoining in so me persons and inhibited it in others, and without statistical signifi cance (p values above 0.5). The stimulating effect of thymidine was si gnificantly inhibited by deoxycytidine (p < 0.05, n = 12) whereas deox yguanosine neither promoted or inhibited the stimulation by thymidine (p = 1, n = 12). Rejoining of DNA strand breaks induced by methyl meth anesulfonate did not appear significantly stimulated or inhibited by a ny of the four deoxynucleosides. Finally, the inhibiting effect of azi dothymidine (AZT) on rejoining of UVC-induced DNA strand breaks was nu llified by the addition of thymidine. In three donors examined, 10(-4) M AZT inhibited the rejoining by about 40-50%. The presence of less t han 10(-5) M thymidine reduced the level of UVC-induced DNA strand bre aks to below the level in control lymphocytes allowed to repair withou t AZT. These results indicate that among the four deoxynucleoside trip hosphates, dTTP has a crucial role on the repair of UVC-induced DNA da mage in quiescent lymphocytes. The results also indicate that an expan sion of the dTTP pool may counteract the inhibiting effect of AZT on D NA repair in quiescent lymphocytes.