Guanine nucleotide depletion primarily causes a drastic inhibition of DNA synthesis, while adenine nucleotide depletion interferes with other vital functions before inhibiting DNA synthesis (M. B. Cohen and W. Sadée, Cancer Res., 43: 1589–1591, 1983). This study addresses the hypothesis that the presence of a large adenine nucleotide pool with direct access to DNA synthesis prevents immediate cessation of DNA synthesis under conditions of adenine starvation, while the small guanine-DNA precursor pool is readily exhausted under guanine starvation. Adenine, guanine, and deoxyadenosine tracers were incubated with asynchronized or synchronized S-49 cells, and tracer progression into cellular nucleotide pools and nucleic acids was measured. Compartmentation of the dATP pool into a functional DNA precursor pool and a general cellular pool could not be demonstrated with [3H]dAdo tracer experiments with S-phase cells. While guanine tracer was incorporated into DNA without delay (<5 min), consistent with a small functional guanine-DNA precursor pool, adenine tracer incorporation into DNA was associated with a substantial delay period (∼30 min) indicative of a large functional adenine-DNA precursor pool. These results suggest that the different size of the functional nucleotide precursor pools with rapid access to DNA synthesis accounts for the dramatic difference in the effects of purine antimetabolites that cause either adenine or guanine starvation.
This study was supported by Public Health Service Research Grants CA-27866 and CA-34304 from the National Cancer Institute, Bethesda, MD.