Study reveals the complete ‘genome guardian’ p53 structure

Researchers uncover the complete 3D structure of gene coding protein p53, marking a significant achievement in biomedical research and a crucial step towards understanding tumour-suppressing proteins.

The Penn State University group fully mapped the structure of p53, or as it’s more widely known as - ‘the guardian of the genome’. Using mutated patient samples, the group were able to 3D map the protein which is essential in protecting the body from DNA replication errors and the onset of cancerous phenotypes.

By triggering cells to either repair or self-destruct, p53 is the powerhouse responsible for guarding the body against daily stresses or long-term damage. It’s when mutations enter this gene coding process where errors can occur, accumulating in the body’s genetic material and leading to serious health conditions. First author of the study, Maria Solares explains how “without understanding the complete structure of the p53, our knowledge of how to deal with it in diseased cells was incomplete.”

The challenge clinicians currently face is to identify and destroy diseased cells that can look similar to surrounding healthy cells. As the tumour-suppressor is commonly present in the molecular structure of cancer progression in patients, understanding the complete structure and functions of p53, and its potential impact on cell integrity is imperative in advancing oncology research.

Solares explains how these new insights into the full-length structure of p53 will help future research on novel therapeutic strategies and hopes it will aid in elevating designs for the clinical community.

In this study, published in the International Journal of Molecular Sciences the researchers set out to define the complete structure of p53, ultimately discovering slight shifts in the 3D structure of mutated p53. These changes can impede communication between the protein and DNA, leading to a breakdown in p53's regulatory and repair processes essential for maintaining healthy cells, explains Deb Kelly, the paper's corresponding author. “It’s hard to understand how things work without the knowledge of their entire physical makeup,” Kelly said.

To understand how mutations impact the structure of p53, the researchers used molecular modelling software to simulate changes in the p53 monomer structure. The findings uncovered a 'closed' dimer structure configuration of p53, unlike other ‘open’ monomer structures that are required to bond with another unit before performing tasks.

To understand how these mutations can render such grave consequences between the protein and DNA, the Penn State researchers hope to continue gathering patient data to expand their breakthrough work and understand the complete picture of p53 maintenance breakdown.