Israeli and German scientists have identified a previously unknown mechanism through which the loss of a key cancer-fighting protein can damage a cell’s DNA, potentially shedding new light on how tumors develop.
The protein, known as p53, is one of the body’s most important defenses against cancer. Produced by the TP53 gene, it acts as a quality-control system, detecting serious problems within cells and preventing damaged cells from multiplying.
The study found that p53 also plays another role: helping ensure that cells do not consume excessive amounts of the building blocks needed to copy their DNA. When p53 is lost or defective, cells produce unusually large amounts of RNA, using up more of these shared building blocks and leaving fewer available for DNA replication.
This shortage can cause DNA damage and chromosome instability, potentially contributing to tumor development.
The study was led by PhD student Wisam Zaatra and Prof. Batsheva Kerem of the Hebrew University of Jerusalem, in collaboration with PhD student George Philippos and Prof. Aurélie Ernst of the German Cancer Research Center and Heidelberg University.
RNA and DNA are both made from basic units called nucleotides. The researchers found that when p53 is lost or defective, the resulting increase in RNA production consumes more nucleotides, leaving fewer available for copying DNA.
The resulting shortage, known as replication stress, can lead to DNA breaks, damage to chromosome ends and the formation of micronuclei—small structures containing misplaced or damaged genetic material. In severe cases, this instability can result in chromothripsis, in which a chromosome shatters and is incorrectly reassembled, a phenomenon observed in many cancers.
The researchers studied cells from patients with Li-Fraumeni syndrome, a rare inherited condition that substantially increases the risk of developing cancer because of a harmful alteration in one copy of the TP53 gene. They also examined other human cell types, including breast cells, and found the same underlying mechanism. An analysis of thousands of tumors across 31 cancer types showed that tumors with damaged or missing p53 tended to have unusually high levels of RNA, reinforcing the link between p53 loss, excess RNA production and problems with DNA replication.
In further experiments, restoring the cells’ supply of DNA building blocks or reducing their excessive RNA production eased replication stress and DNA damage. The findings suggest that the imbalance actively contributes to the damage rather than simply occurring alongside it.
The researchers said the findings could eventually help inform new approaches to treating cancers in which p53 is damaged or missing, potentially by targeting excessive RNA production. They stressed, however, that the discovery does not yet represent a cancer treatment, and that no therapy has emerged from the research so far.
The study was published in the peer-reviewed journal, Molecular Cell.
