Structure-based rescue of common tumor-derived p53 mutants.
The p53 tumor suppressor protein induces cell-cycle arrest or cell death in response to DNA-damaging agents, such as radiation and many of the chemotherapeutics used in cancer therapy. The function of p53 is dependent on its ability to bind DNA in a sequence-specific manner, but in one-half of all human tumors, its sequence-specific DNA binding domain is compromised by single-amino acid substitutions. The nature of these substitutions, which target residues that directly contact DNA or that stabilize the structure of the DNA binding domain, has raised concerns as to whether the function of p53 mutants could ever be rescued. Nevertheless, pharmaceuticals that restore function to p53 mutants could specifically suppress proliferation of cancer cells in patients. To determine whether tumor-derived p53 mutants are irreversibly inactivated, we introduced basic residues in their DNA binding domains, aiming to establish novel contacts between p53 and the DNA phosphate backbone. In three of the seven most common p53 mutants, replacement of Thr284 with Arg significantly enhanced DNA binding affinity, without affecting DNA binding specificity, and rescued their transactivation and tumor suppressor functions. Thus, many tumor-derived p53 mutants retain their sequence-specific DNA binding determinants and can be activated to suppress tumor growth.
Wieczorek
A M
AM
Department of Molecular Oncology, Wistar Institute, Philadelphia, Pennsylvania 19104-4268, USA.
Waterman
J L
JL
Waterman
M J
MJ
Halazonetis
T D
TD
D000495:Allosteric Site; D001483:Base Sequence; D001665:Binding Sites; D004247:DNA / Q000378:metabolism; D016158:Genes, p53; D006801:Humans; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D011485:Protein Binding; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
D016159:Tumor Suppressor Protein p53; D004247:DNA