09 Sep Hebrew University: How p53 Loss Triggers Hypertranscription and Genomic Instability
Hebrew University photo by Maxime Dinshtein
MedicalResearch.com Interview with:
Wisam Zaatra, PhD Student, and Prof. Batsheva Kerem
Hebrew University of Jerusalem
George Philippos, PhD Student, and Prof. Aurélie Ernst
German Cancer Research Center (DKFZ) and Heidelberg University
View the video presentation of this interview
MedicalResearch.com: What is the background for this study? Would you briefly explain what is meant by Li-Fraumeni syndrome?
Response: p53 is one of the most important tumor suppressors and plays a central role in protecting cells from genomic instability. It is defined as the “guardian of the genome” and the loss of its normal function is found in most human cancers. Germline mutations in TP53 cause Li-Fraumeni syndrome (LFS), a rare hereditary cancer predisposition syndrome associated with a high risk of developing multiple cancers, often at a young age. According to the National Cancer Institute, Li-Fraumeni syndrome is caused by inherited mutations in the TP53 gene and significantly increases lifetime cancer risk, with affected individuals frequently developing sarcomas, breast cancers, brain tumors, and leukemias. Our study was motivated by the question of how loss of p53 by itself promotes genomic instability and drives cancer development in LFS patients, as well as in other cellular models with p53 loss. Using patient-derived LFS fibroblasts and other cell models lacking functional p53, we investigated the sequence of events leading from p53 loss to replication stress and chromosomal instability.
MedicalResearch.com: What are the main findings?
Response: We found that loss of p53 causes hypertranscription, an increase in transcriptional activity, which increases nucleotide consumption. This creates a shortage of nucleotides needed for DNA replication, resulting in replication stress and DNA damage. Replication stress subsequently contributes to telomere dysfunction, micronuclei formation, and chromothripsis, a catastrophic form of chromosome rearrangement. Importantly, both nucleotide supplementation and normalization of transcription reduced replication stress and genomic instability. Our findings therefore identify a previously unrecognized role for p53 in coordinating transcription with nucleotide availability to maintain genome stability.
MedicalResearch.com: Is the p53 gene found in particular cells? How does it become damaged?
Response: TP53 is present in essentially all human cells because it is a fundamental tumor-suppressor gene. In Li-Fraumeni syndrome, one TP53 allele carries a germline mutation, meaning that the mutation is inherited and is present in cells throughout the body. In sporadic cancers, TP53 alterations are acquired during a person’s lifetime in individual cells. Loss of functional p53 can then contribute to the accumulation of DNA damage and genomic instability, promoting cancer development.
MedicalResearch.com: How might these findings have clinical implications?
Response: Our findings are currently mechanistic, but they suggest that nucleotide metabolism may represent a potential vulnerability of p53-deficient cancers. Because p53 loss increases transcriptional activity and nucleotide consumption, targeting nucleotide biosynthesis pathways in p53-deficient cancers may provide a potential strategy to selectively target p53-deficient cancer cells. On the other hand, hypertranscription itself may represent a vulnerability that could be exploited therapeutically. Hypertranscription is widespread across many cancers and places a substantial burden on cancer cells. Another possibility we are currently investigating is whether the cellular stress caused by hypertranscription creates additional vulnerabilities that can be exploited to selectively eliminate hypertranscribing cancer cells. An important future goal will be to determine whether these mechanisms can be exploited therapeutically and whether p53-deficient tumors are particularly sensitive to such interventions.
MedicalResearch.com: What recommendations do you have for future research as a result of this study?
Response: An important direction is to understand the molecular basis by which p53 loss induces hypertranscription. Our study shows that this increase in transcription occurs independently of MYC activation, which is known to lead to hypertranscription, but how p53 normally restrains transcriptional activity remains to be determined.
MedicalResearch.com: Is there anything else you would like to add?
Response: We believe the study highlights an important previously unknown function of p53 in maintaining genome stability. Beyond its well-established roles in DNA damage responses, p53 helps maintain a balance between transcription, nucleotide availability, and DNA replication. We hope these findings will stimulate further research into how cellular resource allocation influences genome stability and cancer development.
Disclosures: None disclosed.
Citation:
Zaatra W, Philippos G, Smirnov P, Milo S, Otoničar J, Chan M, Harel M, Devens F, Goldberg T, Eliassaf A, Grimes K, Irony-Tur Sinai M, Sigismondo G, Laue K, Ben-David U, Geiger T, Korbel JO, Krijgsveld J, Shalev O, Kerem B, Ernst A. Hypertranscription caused by p53 deficiency triggers nucleotide insufficiency that induces replication stress and genomic instability. Molecular Cell. 2026;86(17):3411-3430.e14. doi:10.1016/j.molcel.2026.08.003
For a broader overview of how TP53 mutations contribute to hereditary cancer syndromes and what surveillance strategies are recommended for families with Li-Fraumeni syndrome, see this MedicalResearch.com overview of Li-Fraumeni syndrome, TP53 mutations, and hereditary cancer risk.
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Last Updated on September 10, 2026 by Marie Benz MD FAAD