Hebrew University study reveals a new way loss of the p53 "guardian" gene damages DNA

Researchers from the Hebrew University of Jerusalem and the German Cancer Research Center (DKFZ) in Heidelberg reported in September 2026 in the journal Molecular Cell a previously unknown mechanism by which loss of the tumour-suppressor protein p53 damages a cell's genome. The study was led by doctoral student Wisam Zaatra and Prof. Batsheva Kerem of the Hebrew University, together with doctoral student George Philippos and Prof. Aurélie Ernst of the DKFZ and Heidelberg University.

The p53 protein, encoded by the TP53 gene, is often called the guardian of the genome: it senses serious problems inside a cell and stops damaged cells from dividing. It is missing or defective in roughly half of all human cancers. The team discovered that p53 has an additional job. It keeps cells from consuming too many of the nucleotides, the shared chemical building blocks used to make both RNA and DNA. When p53 is lost, cells switch into a state the authors call hypertranscription, producing unusually large amounts of RNA. That uses up nucleotides and leaves too few for copying DNA, a shortage known as replication stress.

Replication stress in turn causes DNA breaks, damage to chromosome ends and the formation of micronuclei, small bodies of misplaced genetic material. In severe cases it can lead to chromothripsis, in which a chromosome shatters and is stitched back together incorrectly, an event seen in many tumours. The researchers showed the mechanism in cells from people with Li-Fraumeni syndrome, an inherited condition in which one copy of TP53 is faulty and cancer risk is very high, and in other human cells including breast cells. An analysis of thousands of tumours across 31 cancer types found that those lacking functional p53 tend to have unusually high RNA levels.

Crucially, when the team restored the supply of nucleotides or dialled down the excess RNA production, replication stress and DNA damage eased, indicating that the imbalance actively drives the damage. The authors caution that the finding is not yet a treatment, but suggest that targeting excess transcription could become a new strategy for cancers in which p53 is broken. Kerem is a leading human geneticist whose earlier work includes co-discovering the gene responsible for cystic fibrosis.