INDUCED N-TERMINAL AND C-TERMINAL CLEAVAGE OF P53 - A CORE FRAGMENT OF P53, GENERATED BY INTERACTION WITH DAMAGED DNA, PROMOTES CLEAVAGE OFTHE N-TERMINUS OF FULL-LENGTH P53, WHEREAS SSDNA INDUCES C-TERMINAL CLEAVAGE OF P53

p53 is able to recognize and bind sites of DNA damage and, in some way , damage to cellular DNA activates a p53 response leading to G(1) arre st or apoptosis. We have previously shown that 'damaged DNA' induces N -terminal cleavage of p53 to generate p40(Delta N) and p35 (core) prot ein products, We now show that the p35 product has protease activity a nd is able to cleave between residues 23 and 24 of full-length p53 to generate a novel product, p50(Delta N23). This activity was inhibited by bestatin, an aminopeptidase inhibitor, Residues 23 and 24 lie withi n the mdm-2 binding domain of p53 and the possibility that p50(Delta N 23) may be resistant to feedback regulation by mdm-2 is discussed. Une xpectedly, interaction with ssDNA induced two further cleavage product s of p53, generated by C-terminal cleavage and designated p50(Delta C) and p40(Delta C). In vivo generation of a C-terminal cleavage product of endogenous p53 similar in size to p50(Delta C) correlated with up- regulation of p21 expression in ML-1 cells exposed to either adriamyci n or cisplatin, The possible significance of the various p53 cleavage products in relation to the cellular response to DNA damage is discuss ed.