Human p53 binds DNA as a protein homodimer but monomeric variants retain full transcription transactivation activity.
Wild-type human p53 protein is able to self-associate and consists predominantly of homotetramers in solution. In earlier work we identified the protein sequence motifs involved in p53 quaternary structure and showed that while monomeric p53 protein retains tumour suppressor function, monomeric tumour mutant p53 lacks dominant transforming activity. In this report we use point mutated and truncated cDNA genes encoding self-association defective human p53 proteins to investigate the relationship between p53 protein quaternary structure and the associated activities of transcription transactivation and target specific DNA binding. We show that p53 binds to a target oligonucleotide as a protein homodimer and that p53 dimerisation is required for detectable DNA binding. We found no evidence for p53 tetramer: DNA complexes and we suggest that the quaternary structure status of p53 may regulate a DNA binding associated activity. Monomeric p53 proteins failed to bind DNA in these assays but exhibited increased transactivating activity. Thus, both transcription transactivation and tumour suppressor functions act independently of p53 protein self-association and DNA binding. We propose that our results validate the p53 dimerisation motif as a target for rational anticancer drug design. We predict that compounds able to block p53 dimer assembly would inhibit the dominant transforming activities of mutant p53 in tumours retaining expression of a mutant allele, while leaving intact the wild-type p53 associated activities of transcription transactivation and transformation suppression in unaffected tissue.
Tarunina
M
M
Cell Proliferation Laboratory, Marie Curie Research Institute, Oxted, Surrey.
Jenkins
J R
JR
D001483:Base Sequence; D004247:DNA / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D011401:Promoter Regions, Genetic; D015534:Trans-Activators / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000378:metabolism*
D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D004247:DNA