The ataxia-telangiectasia gene product may modulate DNA turnover and control cell fate by regulating cellular redox in lymphocytes

The ATM kinase, when activated postnatally, exerts multiple functions to pr event the onset of ataxia-telangiectasia (AT), Using freshly isolated thymo cytes from Atm-/- mice that were under stress during postnatal differentiat ion, we noted that thiol redox activity, as indicated by reduction of the t ebrazolium MTS, and DNA turnover activity, as indicated by incorporation of [H-3]thymidine into DNA, were both greatly increased compared with activit ies in thymocytes from Atm+/+ mice, This increased thymidine incorporation could be suppressed by the thiol N-acetylcysteine, In primary noncycling sp lenocytes, mitogens proportionally increased both the rate of [H-3]thymidin e incorporation and the rate of reduction of MTS, The mitogen-induced activ ities in splenocytes were not affected by ATM but were suppressed by the ca lcineurin-dependent inhibitor FK-506, which has no effect on these activiti es in thymocytes, These findings suggest that increased [H-3]thymidine inco rporation and reducing power indicate increased cell cycling in mitogenical ly stimulated splenocytes, whereas these two indicators represent increased FK-506-independent DNA turnover activities in thymocytes, Thus, a primary function of ATM is to activate the redox-sensitive checkpoint required for down-regulation of DNA turnover activities in developing lymphocytes, Cell- cycling checkpoints in undamaged quiescent lymphocytes are not activated by ATM with mitogenic stimulation. ATM may suppress abnormal DNA turnover and the resultant oncogenesis by regulating cellular thiol redox pathways.