Although zinc is known to be involved in cell proliferation and DNA synthesis, the mechanism by which zinc may regulate these processes is not understood. We have studied the role of zinc on cell proliferation and gene expression of a DNA synthesizing enzyme, deoxythymidine kinase (TK), in a T helper human malignant lymphoblastoid cell line (HUT-78). In zinc-deficient and zinc-sufficient media, the cell doubling time (mean +/- SD) of HUT-78 was 59 +/- 8 hours and 32.6 +/- 6 hours, respectively. The effect of zinc was T cell specific, inasmuch as the cell growth of another T malignant lymphoblastoid cell line, MOLT-3 (immature T cells), was not affected by zinc deficiency. Iron, copper, or manganese did not completely correct the cell growth of zinc-deficient HUT-78 cells. TK activity and the relative accumulation of TK-mRNA were significantly decreased in zinc-deficient cells during the G1 phase of cell cycle in comparison with zinc-sufficient cells. Nuclear run-on experiments and actinomycin-D studies showed that the transcription of TK-mRNA was affected adversely by zinc deficiency. Cell cycle studies showed that more zinc-deficient cells remained in S phase and did not undergo mitosis in comparison with zinc-sufficient cells. In conclusion, our data show that zinc is a T cell-specific growth factor and that a decreased gene expression of DNA-synthesizing enzyme TK in zinc-deficient HUT-78 cells in G1 phase affected adversely the DNA synthesis in S phase and delayed cell cycle.