DEFECT IN MULTIPLE CELL-CYCLE CHECKPOINTS IN ATAXIA-TELANGIECTASIA POSTIRRADIATION

The recent description of a novel gene (ATM) mutated in ataxia-telangi ectasia (A-T), with homologies to genes encoding proteins involved in both G(1)/S and G(2)/M checkpoint control, points to a common defect i n cell cycle control in A-T operating through the cyclin-dependent kin ases. In this report we demonstrate that cyclin-dependent kinases are resistant to inhibition by ionizing radiation exposure in A-T cells, a nd this appears to be due to insufficient induction of WAF1. Exposure of control lymphoblastoid cells to radiation during S phase and in G(2 ) phase causes a rapid inhibition of cyclin A-Cdk2 and cyclin B-Cdc2 a ctivities, respectively, Irradiation led to a 5-20-fold increase in Cd k-associated WAF1 in these cells, which accounts at least in part for the decrease in cyclin-dependent kinase activity. In contrast, radiati on did not inhibit any of the cyclin-dependent kinase activities in S phase or G(2) phase in A-T cells at short times after irradiation nor was there any significant change in the level of Cdk-associated WAF1 c ompared to unirradiated cells. These results are similar to those repo rted previously for the G(1) checkpoint and provide additional evidenc e for the involvement of ATM at multiple points in cell cycle regulati on.