Dose-dependent effects of DNA-damaging agents on p53-mediated cell cycle arrest

We examined the dose-dependent effects of DNA-damaging agents on G(1) arres t in isogenic human cell lines differing in their p53 status. As expected, 5 or 20 Gy of ionizing radiation induced a p53-dependent G(1) arrest. In co ntrast, UV light or actinomycin D induced a modest G(1) arrest that was p53 -dependent only at lower doses. At higher doses, cells were arrested in G(1 ) in a p53-independent manner coinciding with inhibition of RNA synthesis a nd abolished cyclin E expression. Interestingly, expression of cyclin E was enhanced after exposure to moderate doses of UV light and actinomycin D, a nd this enhancement was suppressed by wild-type p53, We propose that agents inducing transcription-blocking DNA lesions will at higher doses inhibit t he progression of cells into S phase by a p53-independent mechanism involvi ng the attenuation of E2F-mediated transcription of genes, such as cyclin E .