DNA lesion bypass polymerases and 4'-thio-β-Darabinofuranosylcytosine (T-araC)

The 4'-thio-β-D-arabinofuranosylcytosine (T-araC) is a newly developed nucleoside analog that has shown promising activity against a broad spectrum of human solid tumors in both cellular and xenograft mice models. TaraC shares similar structure with another anticancer deoxycytidine analog, β-D-arabinofuranosylcytosine (araC, cytarabine), which has been used in clinics for the treatment of acute myelogenous leukemia but has a very limited efficacy against solid tumors. T-araC exerts its anticancer activity mainly by inhibiting replicative DNA polymerases from further extension after its incorporation into DNA. DNA lesion bypass polymerases can manage the DNA lesions introduced by therapeutic agents, such as cisplatin and araC, therefore reduce the activity of these compounds. In this study, the potential relationships between the lesion bypass Y-family DNA polymerases η, ι and κ (pol η, pol ι, and pol κ) and T-araC were examined. Biochemical studies indicated that the triphosphate metabolite of T-araC is a less preferred substrate for the Y-family polymerases. In addition, cell viability study indicated that pol η deficient human fibroblast cells were more sensitive to T-araC when compared with the normal human fibroblast cells. Together, these results suggest that bypass polymerases reduced cell sensitivity to T-araC through helping cells to overcome the DNA damages introduced by T-araC.