DNTP POOLS IMBALANCE AS A SIGNAL TO INITIATE APOPTOSIS

Fidelity in DNA synthesis and repair is largely dependent on a balance d supply of deoxynucleotide triphosphate (dNTP) pools. Results from di fferent groups have shown that alterations in dNTP supply result in DN A fragmentation and cell death with characteristics of apoptosis. We h ave recently shown that in apoptosis driven by deprivation of interleu kin-3 (IL-3) in a murine hemopoietic cell line, there is a rapid imbal ance in the availability of dNTP that precedes DNA fragmentation. In t hese cells, dNTP pool balance is closely coupled to the function of th e salvage pathway of dNTP synthesis. Apoptosis, induced by treatment o f these cells with drugs that inhibit the de novo dNTP synthesis, is p revented when dNTP precursors are supplied through the salvage pathway . IL-3 regulates thymidine kinase activity, suggesting that alteration s in dNTP metabolism after IL-3 deprivation could be a relevant event in the commitment of hemopoietic cells to apoptosis.