Journal Article

DKFZ-2026-02183

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Hypertranscription caused by p53 deficiency triggers nucleotide insufficiency that induces replication stress and genomic instability.

Zaatra, W. ; Philippos, G. (First author)DKFZ* ; Smirnov, P.DKFZ* ; Milo, S. ; Otonicar, J.DKFZ* ; Chan, M.DKFZ* ; Harel, M. ; Devens, F.DKFZ* ; Goldberg, T. ; Eliassaf, A. ; Grimes, K. ; Irony-Tur Sinai, M. ; Sigismondo, G.DKFZ* ; Laue, K. ; Ben-David, U. ; Geiger, T. ; Korbel, J.DKFZ* ; Krijgsveld, J.DKFZ* ; Shalev, O. ; Kerem, B. ; Ernst, A. (Last author)DKFZ*

2026
Cell Press [Cambridge, Mass.]

Abstract: p53 plays a central role in the DNA damage response, inducing repair, cell-cycle arrest or apoptosis. Its loss is associated with replication stress and genomic instability. While several underlying mechanisms were suggested, the primary triggers of catastrophic genomic events like chromothripsis, a known driver of tumorigenesis linked with p53 loss, are still unclear. Using p53-depleted epithelial cells and fibroblasts, as well as patient-derived fibroblasts with germline p53 variants that spontaneously undergo chromothripsis, we found that p53 loss causes hypertranscription and increased nucleotide consumption. The resulting nucleotide shortage induces replication stress, causing telomere dysfunction, micronuclei formation, and chromothripsis. These effects were rescued by nucleoside supplementation or normalization of transcription levels, demonstrating a causal link between transcriptional activity, nucleotide availability, and genome stability. Emerging chromothriptic clones displayed restored DNA replication, telomere stabilization, and extrachromosomal DNA, suggesting key features that support clonal selection. We identify nucleotide pool homeostasis as a critical p53 function that suppresses replication stress, prevents chromothripsis, and protects against early tumorigenesis.

Keyword(s): Genomic Instability (MeSH) ; Humans (MeSH) ; Tumor Suppressor Protein p53: genetics (MeSH) ; Tumor Suppressor Protein p53: deficiency (MeSH) ; Tumor Suppressor Protein p53: metabolism (MeSH) ; DNA Replication (MeSH) ; Chromothripsis (MeSH) ; DNA Damage (MeSH) ; Fibroblasts: metabolism (MeSH) ; Fibroblasts: pathology (MeSH) ; Transcription, Genetic (MeSH) ; Nucleotides: metabolism (MeSH) ; Nucleotides: deficiency (MeSH) ; Nucleotides: genetics (MeSH) ; Telomere: metabolism (MeSH) ; Telomere: genetics (MeSH) ; Extrachromosomal DNA (MeSH) ; cancer ; chromothripsis ; genomic instability ; hypertranscription ; nucleotide insufficiency ; p53 deficiency ; replication stress ; Tumor Suppressor Protein p53 ; TP53 protein, human ; Nucleotides ; Extrachromosomal DNA

Note: #EA:B420#LA:B420 / #DKTKZFB26#

---

Contributing Institute(s):

1. Genominstabilität in Tumoren (B420)
2. Mechanismen der genetischen Variation und Datenwissenschaft (B480)
3. Proteomik von Stammzellen und Krebs (B230)
4. DKTK HD zentral (HD01)

Research Program(s):

1. 312 - Funktionelle und strukturelle Genomforschung (POF4-312) (POF4-312)

Appears in the scientific report 2026

---

Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 15 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

---