A p53-independent damage-sensing mechanism that functions as a checkpoint at the G(1)/S transition in Chinese hamster ovary cells

In response to a moderate dose of radiation, asynchronous mammalian cell populations rapidly and transiently down-regulate the rate of DNA synthesis to ≈50% of preirradiation values. We show here that only half of the reduction in overall replication rate can be accounted for by direct inhibition of initiation at origins in S-phase cells. The other half results from the operation of a newly defined cell cycle checkpoint that functions at the G(1)/S transition. This checkpoint senses damage incurred at any time during the last 2 hr of G(1) and effectively prevents entry into the S period. The G(1)/S and S-phase checkpoints are both p53-independent and, unlike the p53-mediated G(1) checkpoint, respond rapidly to radiation, suggesting that they may represent major damage-sensing mechanisms connecting the replication machinery with DNA repair pathways.