Scientists uncover a molecular mechanism linking loss of p53 to DNA damage and genomic instability

A new study finds that when p53, one of the most important cancer-protecting genes, stops working, cells produce too much RNA and consume excessive amounts of the building blocks needed to copy their DNA. This shortage disrupts DNA replication, leading to DNA damage, chromosome instability and major genetic changes that can promote cancer development. The findings reveal a previously unknown way in which p53 protects genome integrity and point to new avenues for understanding cancers in which p53 is damaged or missing.

The study was led by the PhD student Wisam Zaatra and Prof. Batsheva Kerem of the Hebrew University of Jerusalem, in collaboration with the PhD student George Philippos and Prof. Aurélie Ernst of the German Cancer Research Center (DKFZ) and Heidelberg University. The researchers investigated the consequences of p53 deficiency and how it affects the maintenance of genome integrity.

p53 is sometimes called the “guardian of the genome” because it helps protect cells when their DNA is damaged. When DNA is damaged, p53 can stop a cell from dividing, allow time for repair, or trigger cell death if the damage is too severe.

The new research shows that p53 has another important role: it helps maintain the balance between RNA production and the supply of building blocks needed to replicate DNA, thereby protecting genome stability.

Both RNA and DNA are made from basic building blocks called nucleotides. When p53 is lost, cells produce too much RNA and consume excessive amounts of these building blocks. Too few are then available for DNA replication.

This shortage places the cell under replication stress and can cause DNA breaks, damage to chromosome ends and the formation of micronuclei, small structures containing misplaced or damaged DNA.

In extreme cases, this instability can lead to chromothripsis, in which a chromosome is shattered into many pieces and incorrectly reassembled. Such extensive genetic alterations are found in many cancers and can contribute to tumor development.

The researchers studied cells from people with Li-Fraumeni syndrome, a rare inherited condition that greatly increases the risk of cancer. People with this syndrome carry a harmful alteration in one copy of the TP53 gene.

By following these cells over time, the team was able to observe early changes associated with p53 deficiency and genomic instability. The researchers also examined other human cell types, including breast cells, and found the same basic mechanism. Analysis of thousands of tumors across 31 cancer types showed that tumors with damaged or missing p53 also tended to produce unusually high levels of RNA.

The team then added nucleosides, the building blocks used to produce nucleotides, to cells lacking p53. Restoring the supply reduced replication stress and DNA damage. Reducing the cells’ excessive RNA production produced a similar protective effect.

The findings do not yet provide a new cancer treatment. However, they reveal a previously unknown mechanism by which p53 protects the genome and suggest that the way cancer cells produce and use nucleotide, and balance RNA production with DNA replication, may be an important area for future research.