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 ce ll populations rapidly and transiently down-regulate the rate of DNA s ynthesis to approximate to 50% of preirradiation values. We show here that only half of the reduction in overall replication rate can be acc ounted for by direct inhibition of initiation at origins in S-phase ce lls. The other half results from the operation of a newly defined cell cycle checkpoint that functions at the G(1)/S transition. This checkp oint senses damage incurred at any time during the last 2 hr of G(1) a nd effectively prevents entry into the S period. The G(1)/S and S-phas e 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 m achinery with DNA repair pathways.