Mechanism of inhibition of DNA ligase in Ara-C treated cells.

The activity of DNA ligase, the enzyme involved in ligation of DNA fragments and also in DNA repair is inhibited by Ara-C. The exposure of two human leukemic cell lines, K562 and HL-60 to 10(-5) M Ara-C for 3 h, induces a decrease of DNA ligase activity by 40% in K562 and 92% in HL-60. This decreased activity is due to an inhibition by Ara-CTP of the ligase-adenylate complex generation, the crucial step in the action of this enzyme. The activity of the semi-purified ligase as well as the formation of ligase-adenylate complex are decreased in the presence of Ara-CTP. These results demonstrate that Ara-C via its active form Ara-CTP inhibits DNA ligase activity through the inhibition of the ligase-adenylate complex. Other inhibitors of DNA synthesis, such as hydroxyurea, do not exert the same inhibitory effect. The inhibition of DNA ligase activity may be partly responsible for the cytotoxicity of Ara-C.