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 now show that interaction with non-specific DNA, but not specific DNA targets, induces selective proteolysis of p53 to give a 40 kDa fragment, comprising the core plus C-terminus, and a 35 kDa conformationally intact core domain. Proteolytic cleavage was limited and yielded roughly equivalent proportions of full length p53 and the 40 kDa and 35 kDa fragments. Significantly, both 40 kDa and 35 kDa products were activated for sequence-specific DNA binding. Similar p53-related products were induced by exposure of cells to DNA damage. We propose that some functions of p53 can be activated by proteolytic processing and that this may be important in the cellular response to DNA damage.
Molinari
M
M
YCRC P53 Research Group, Department of Biology, University of York, UK.
Okorokov
A L
AL
Milner
J
J
D016475:3T3 Cells; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001483:Base Sequence; D002945:Cisplatin / Q000494:pharmacology; D004247:DNA / Q000187:drug effects / Q000378:metabolism*; D004249:DNA Damage; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D008970:Molecular Weight; D015345:Oligonucleotide Probes / Q000235:genetics; D010446:Peptide Fragments / Q000378:metabolism* / Q000502:physiology; D011480:Protease Inhibitors / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism* / Q000502:physiology
D000970:Antineoplastic Agents; D015345:Oligonucleotide Probes; D010446:Peptide Fragments; D011480:Protease Inhibitors; D016159:Tumor Suppressor Protein p53; D004247:DNA; D002945:Cisplatin