Inhibition of DNA repair by trifluoperazine.
We examined the possible role of calmodulin in the excision repair of ultraviolet light-induced pyrimidine dimers in damaged DNA by means of specialized assay systems. These assays included bromodeoxyuridine photolysis, dimer chromatography and cytosine arabinoside incorporation in conjunction with hydroxyurea. The calmodulin antagonist, trifluoperazine, and the calcium-chelating agent, EGTA, were employed to ascertain what affect calmodulin played in the repair process. Normal human fibroblast cells were used in all studies described in this report. After exposure to 10 J/m2 of 254 nm light, we observed a decrease of about 30% in the number of single-strand breaks produced in the presence of 25 microM trifluoperazine (1.9 vs. 3.3) in controls although the numbers of bases re-inserted in the repaired regions were similar (64 vs. 72). Measurement of thymine-containing dimers remaining throughout a 24 h time period indicated a 30% difference in the excision of dimers when tested with either EGTA or trifluoperazine. We also observed a significant decrease in the number of cytosine arabinoside arrested repair sites in the presence of either EGTA or trifluoperazine. The results are discussed with relation to the possibility of calmodulin altering the initial incision by repair endonuclease.
D001973:Bromodeoxyuridine / Q000378:metabolism; D002147:Calmodulin / Q000502:physiology; D002478:Cells, Cultured; D003561:Cytarabine / Q000494:pharmacology; D004247:DNA / Q000528:radiation effects; D004260:DNA Repair / Q000187:drug effects*; D003864:Depression, Chemical; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D011740:Pyrimidine Dimers / Q000378:metabolism; D014268:Trifluoperazine / Q000494:pharmacology*; D014466:Ultraviolet Rays
D002147:Calmodulin; D011740:Pyrimidine Dimers; D003561:Cytarabine; D014268:Trifluoperazine; D004247:DNA; D001973:Bromodeoxyuridine