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
.