STRUCTURES AND FUNCTIONS OF THE TUMOR-SUPPRESSOR P53

The tumour suppressor p53 plays a crucial role in the cellular respons e to DNA damage. The p53 protein is able both to detect sites of DNA d amage and to interact with DNA in a sequence-specific manner and funct ion in the regulation of target gene expression. These two properties map to discrete functional domains of the protein, the C-terminus and the central core domain respectively. They are essential for integrati on of a normal cellular response to DNA damage, with initiation of eit her G1 cell cycle arrest or apoptosis. This review considers the domai n structure of p53 in relation to the protein's various functions, tog ether with the importance of tertiary structure and conformational fle xibility. The precise regulation of p53 function remains to be establi shed, although the protein is known to be phosphorylated/de-phosphoryl ated by a number of specific protein kinases/phosphatases. A recent di scovery indicates that p53 may be activated by autoproteolysis and tha t proteolytic cleavage is induced by direct interaction with sites of DNA damage. This process is reminiscent of the bacterial Lex A system and would provide one mechanism for activation of p53 in response to c ellular DNA damage.