CONTROL OF G(1) ARREST AFTER DNA-DAMAGE

The temporal relationship between DNA damage and DNA replication may be critical in determining whether the genetic changes necessary for cellular transformation occur after DNA damage. Recent characterization of the mechanisms responsible for alterations in cell-cycle progression after DNA damage in our laboratory have implicated the p53 (tumor suppressor) protein in the G(1) arrest that occurs after certain types of DNA damage. In particular, we found that levels of p53 protein increased rapidly and transiently after nonlethal doses of gamma irradiation (XRT) in hematopoietic cells with wild-type, but not mutant, p53 genes. These changes in p53 protein levels were temporally linked to a transient G(1) arrest in these cells. Hematopoietic cells with mutant or absent p53 genes did not exhibit this G(1) arrest, through they continued to demonstrate a G(2) arrest. We recently extended these observations of a tight correlation between the status of the endogenous p53 genes and this G(1) arrest after XRT and this cell-cycle alteration after XRT was then established by transfecting cells lacking endogenous p53 genes with a wild-type gene and observing acquisition of the G(1) arrest and by transfecting cells processing endogenous wild-type p53 genes with a mutant p53 gene and observing loss of the G(1) arrest after XRT. These observations and their significance for our understanding of the mechanisms of DNA damage-induced cellular transformation are discussed.