INACTIVATION OF P53 IN NORMAL HUMAN-CELLS INCREASES G(2) M ARREST ANDSENSITIVITY TO DNA-DAMAGING AGENTS/

p53 mutations are found in about 70% of human cancers. In order to eva luate the role of these mutations in response to chemotherapeutic agen ts, it is important to distinguish between p53 response to DNA-damagin g agents in normal and in tumour cells. Here, using normal human fibro blasts (NHFs), we show that cisplatin and UV radiation induce G(2)/M a rrest which is temporally linked to p53-protein induction, To study th e contribution of p53 to this G(2)/M arrest, we inhibited p53 inductio n in NHFs using p53 anti-sense oligonucleotides, Following exposure of NH Fs to UV radiation, the inhibition of p53-protein induction leads to a greater accumulation of cells in the G(2)/M phase, but also to a decreased fraction of cells in the G(1) phase, We propose that p53 doe s not induce G(2)/M arrest directly, and that the extent of this arres t may depend on the fraction of cells that do not stop at the G(1) pha se following exposure to DNA-damaging agents. Furthermore, inhibition of p53-protein induction leads to increased sensitivity of NHFs to UV radiation. These results suggest that inhibition of p53 protein enhanc es sensitivity to DNA-damaging agents in normal human cells. (C) 1998 Wiley-Liss, Inc.