INTERACTION WITH DAMAGED DNA INDUCES SELECTIVE PROTEOLYTIC CLEAVAGE OF P53 TO YIELD 40 KDA AND 35 KDA FRAGMENTS COMPETENT FOR SEQUENCE-SPECIFIC DNA-BINDING

The p53 protein binds sites of primary DNA damage via its C-terminus. This interaction in some way activates sequence-specific binding (via the central core domain) and transactivation of p53 target genes. We n ow show that interaction with non-specific DNA, but not specific DNA t argets, induces selective proteolysis of p53 to give a 40 kDa fragment , comprising the core plus C-terminus, and a 35 KDa conformationally i ntact core domain. Proteolytic cleavage was limited and yielded roughl y equivalent proportions of full length p53 and the 40 kDa and 35 kDa fragments. Significantly, both 40 kDa and 35 kDa products were activat ed for sequence-specific DNA binding. Similar p53-related products wer e induced by exposure of cells to DNA damage. We propose that some fun ctions of p53 can be activated by proteolytic processing and that this may be important in the cellular response to DNA damage.