STRUCTURE-BASED RESCUE OF COMMON TUMOR-DERIVED P53 MUTANTS

The p53 tumor suppressor protein induces cell-cycle arrest or cell dea th in response to DNA-damaging agents, such as radiation and many of t he chemotherapeutics used in cancer therapy(1,2). The function of p53 is dependent on its ability to bind DNA in a sequence-specific manner( 3), but in one-half of all human tumors, its sequence-specific DNA bin ding domain is compromised by single-amino acid substitutions(4). The nature of these substitutions, which target residues that directly con tact DNA or that stabilize the structure of the DNA binding domain(5), has raised concerns as to whether the function of p53 mutants could e ver be rescued(6). Nevertheless, pharmaceuticals that restore function to p53 mutants could specifically suppress proliferation of cancer ce lls in patients. To determine whether tumor-derived p53 mutants are ir reversibly inactivated, we introduced basic residues in their DNA bind ing domains, aiming to establish novel contacts between p53 and the DN A phosphate backbone. In three of the seven most common p53 mutants, r eplacement of Thr284 with Arg significantly enhanced DNA binding affin ity, without affecting DNA binding specificity, and rescued their tran sactivation and tumor suppressor functions. Thus, many tumor-derived p 53 mutants retain their sequence-specific DNA binding determinants and can be activated to suppress tumor growth.