POLY(A)+RNA AS A POSSIBLE TARGET FOR DEOXYADENOSINE INDUCED G1/G0 LYMPHOTOXICITY

In the presence of inhibitors of the enzyme adenosine deaminase (ADA), micromolar concentrations of 2′-deoxyadenosine (dAdo) are toxic to cultured T-leukemic lymphoblasts1. Lymphotoxicity has been attributed to allosteric inhibition of ribonucleotide reductase by accumulated dATP, with resultant inhibition of DNA synthesis. There is now evidence, however, that dAdo is lymphotoxic independent of any inhibition of DNA synthesis.In the presence of ADA inhibitors, micromolar concentrations of dAdo are toxic to non-dividing human lymphoid cells3,4, and human T-lymphoblasts exposed to cytostatic concentrations of dAdo arrest in G1 phase5. We sought to determine if these effects of dAdo were due to effects of dATP on polyadenylated (poly(A)+)RNA metabolism, analogous to the effects of 3′-dAdo (cordycepin). The cordycepin metabolite, 3′-dATP, preferentially inhibits the synthesis and polyadenylation of poly (A)+ RNA and there is evidence that 3′-dATP is incorporated at the 3′terminus of poly(A) segments, leading to premature chain termination6,7. Despite marked differences in the gross DNA/RNA perturbations seen in dAdo and cordycepin treated cells, we show that dAdo is also terminally incorporated into poly(A) segments, suggesting another possible mechanism for dAdo lymphotoxicity.