CELL-CYCLE REGULATION IN RESPONSE TO DNA-DAMAGE IN MAMMALIAN-CELLS - A HISTORICAL-PERSPECTIVE

Cell cycle delay has long been known to occur in mammalian cells after exposure to DNA-damaging agents. It has been hypothesized that the fu nction of this delay is to provide additional time for repair of DNA b efore the cell enters critical periods of the cell cycle, such as DNA synthesis in S phase or chromosome condensation in G2 phase. Recent ev idence that p53 protein is involved in the delay in G1 in response to ionizing radiation has heightened interest in the importance of cell c ycle delay, because mutations in p53 are commonly found in human cance r cells. Because mammalian cells defective in p53 protein show increas ed genomic instability, it is tempting to speculate that the instabili ty is due to increased chromosome damage resulting from the lack of a G1 delay. Although this appears at first glance to be a highly plausib le explanation, a review of the research performed on cell cycle regul ation and DNA damage in mammalian cells provides little evidence to su pport this hypothesis. Studies involving cells treated with caffeine, cells from humans with the genetic disease ataxia-telangiectasia, and cells that are deficient in p53 show no correlation between G1 delay a nd increased cell killing or chromosome damage in response to ionizing radiation. Instead, G1 delay appears to be only one aspect of a compl ex cellular response to DNA damage that also includes delays in S phas e and G2 phase, apoptosis and chromosome repair. The exact mechanism o f the genomic instability associated with p53, and its relationship to the failure to repair DNA before progression through the cell cycle, remains to be determined.