More than half of human cancers involve mutations in the p53 tumor-suppressor gene, suggesting the critical role played by the normal p53 protein in defending against cancer.
Similarly, roughly 95 percent of cancer-causing mutations in the p53 protein occur in its DNA-binding core domain, pointing to this region of the p53 protein as being pivotal to its anti-cancer activity.
Clearly, a detailed view of the p53 protein in direct contact with DNA could provide important insights into preventing and treating an array of human cancers. To date, however, despite having learned a good deal about the protein's biochemistry over the years, scientists have been unable to "see" the protein - using the tools of structural biology - bound to DNA in its naturally occurring form. This naturally occurring form contains a pairing of two p53 proteins, called a dimer, that then binds to a second p53 dimer in a similar way to create the precisely oriented four-protein complex, called a tetramer, that binds DNA.
Now, in a new study featured as a "paper of the week" and on the cover of the July 21 issue of the Journal of Biological Chemistry, researchers at The Wistar Institute have successfully determined the three-dimensional structure of the p53 protein bound as a dimer to DNA and used the structure to produce an accurate model of the p53 tetramer bound to DNA.
"The bottom line is that we now have a detailed picture of how p53 binds DNA," says Ronen Marmorstein, Ph.D., a professor in the Gene Expression and Regulation Program at Wistar and senior author on the study. "Given the fact that p53 is an important tumor suppressor that is mutated in the majority of human cancers, this will undoubtedly be useful information."
Earlier work had shown how p53 binds to DNA as a stand-alone entity, a form that does not represent the natural state of p53 binding to DNA. The present work captures p53 bound to DNA in its natural dimeric units and thus allows Marmorstein and colleagues to make new and potentially significant insights into p53 function.