First labelled an oncogene upon its discovery in 1979, p53 (or TP53 in humans), was correctly re-labelled a tumour suppressor a decade later following the discovery that the gene previously being studied was, ironically, a mutant. Now realised as the most common mutated gene, found in a staggering 50% of cancers, p53 is a keystone in the face of cancer. Its structure and functions continue to be delved into. Amino acids, genome stability, tumour suppression, iPS?
53 kilo-Daltons in size, 11 exons and 10 introns, p53 gene is located on chromosome 17. Using a clone isolated from a cDNA library of simian virus 40- transformed human fibroblasts, Mcbride et al. (1985), identified the location of p53 gene. Using karyotypic analysis and Southern analyses, they narrowed down the exact position of the p53 gene to the most distal band on the short arm of chromosome 17- the telomeric band 17p13.
Structurally abundant in domains, p53 has three main functional domains and 393 amino acids in total. The first domain, the N-terminal (NH2 terminal) houses amino acids that are important in transactivation. In vivo, p53 requires amino acids F19, L22, and W23 found in the N-terminal for transcriptional activation (Lin et al., 1995). Present also, are the amino acid residues 22 and 23, although positive- regulators of transcriptional activity, are later to play a role in the negative-regulation of p53. In highlighting similarities between p53 protein-DNA interactions to other protein-DNA complexes, Cho et al. (1994), point out that p53 uses a loop packing at the NH2-terminal part of the alpha helix to make extra connections to the bases in the major groove of DNA.
The C-terminal (carboxyl terminal) —61 important amino acids— catalyses the reassociation of single stranded DNA or RNA to double strands, especially to DNA ends and internal deletion loops in DNA. It also oversees the tetramerization and oligomerization functions and contains two beta sheets and two alpha helixes and the amino acids 324-355 necessary for these functions (Lee et. al, 1995). Unlike its counterparts, mutations are less frequent in this domain. The tetramerization domain, as it is commonly referred to, is connected to the last domain by a chain of 37 residues.
Unarguably, the sequence specific DNA binding domain or core domain is the most important domain of p53 since most of the missense mutations (90%) of p53 occur here. It was proposed that understanding this specific domain better would gain further insight into its DNA binding capacity and the extent to which mutations affected this function. Consequently, Cho et al., (1994), crystalized the core domain to achieve just this. “The crystal structure of a complex containing the core domain of human p53 and a DNA binding site has been determined at 2.2 angstroms resolution and refined to a crystallographic R factor of 20.5%” (Cho et al., 1994). Found nestled between amino acid residues 102 and 292, it is...