ROLE OF WILD-TYPE P53 IN THE G(2) PHASE - REGULATION OF THE GAMMA-IRRADIATION-INDUCED DELAY AND DNA-REPAIR

Upregulation of the p53 protein was shown to induce cell cycle arrest at the G(1)/S border and in some cases at the G(2)/M border. Furthermo re, it was suggested that p53 is associated with the induction of the various DNA repair pathways. Previously, we demonstrated that cells co expressing endogenous wild type p53 protein, together with dominant ne gative mutant p53, exhibit deregulation of apoptosis, G(1) arrest and delay in G(2) following gamma-irradiation. In the present study, we in vestigated the role of p53 protein in the DNA damage response at the G (2) phase. Using p53-null, wild type p53 and mutant p53-producer cell lines, we found that the two C-terminally spliced p53 forms could prev ent gamma-irradiation induced mutagenesis prior to mitosis, at the G(2 )/M checkpoint. We found that at the G(2) phase, p53 may facilitate re pair of DNA breaks giving rise to micronuclei, and regulate the exit f rom the G(2) checkpoint. At the G(1) phase, only the regularly spliced form of p53 caused growth arrest. In contrast, both the regularly and the alternatively spliced p53 forms directed postmitotic micronucleat ed cells towards apoptosis. These results provide a functional explana tion for the cell cycle-independent expression of p53 in normal cyclin g cells, as well as in cells where p53 is up-regulated, following DNA damage.