DNA-DAMAGE AND P53-MEDIATED CELL-CYCLE ARREST - A REEVALUATION

Most mammalian cells exhibit transient delays in the G(1) and G(2) pha ses of the cell cycle after treatment with radiation or radiomimetic c ompounds, p53 is required for the arrest in G(1), which provides time for DNA repair, Recently, a role of p53 in the G(2)/M transition has a lso been suggested, However, it has been reported that the presence of functional p53 does not always correlate with the induction of these checkpoints, To precisely assess the role of p53 in activating cell cy cle checkpoints and in cell survival after radiation, we studied the r esponse of two isogenic human fibrosarcoma cell lines differing in the ir p53 status (wild type or mutant), We found that when irradiated cel ls undergo a wild-type p53-dependent G(1) arrest, they do not subseque ntly arrest in G(2). Moreover, wild-type p53 cells irradiated past the G(1) checkpoint arrest in G(2) but do not delay in the subsequent G(1 ) phase, Furthermore, in these cell lines, which do not undergo radiat ion-induced apoptosis, the wild-type p53 cell line exhibited a greater radioresistance in terms of clonogenic survival, These results sugges t that the two checkpoints may be interrelated, perhaps through a cont rol system that determines, depending on the extent of the damage, whe ther the cell needs to arrest cell cycle progression at the subsequent checkpoint for further repair, p53 could be a crucial component of th is control system.