The p53 DNA-Binding (Core) Domain can form a prion that seeds prion formation in full-length p53

Authors:

Mathilde Kadouch1, Christelle Marchal1, Sei-Kyoung Park2, Sangeun Park2, Sabine Castano1, Susan W. Liebman2 and Christophe Cullin1

doi: 10.15698/mic2026.10.887
Volume 13, pp. 340 to 357, published 02/10/2026.

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Affiliations:

1 Univ. Bordeaux, CNRS, Bordeaux INP, CBMN, UMR 5248, F-33600 Pessac, France. 2 Department of Pharmacology, University of Nevada, Reno, United States of America.

Keywords: 

yeast, p53, prion, prionization frequency.

Corresponding Author(s):

Christophe Cullin, Institute of Chemistry & Biology of Membranes & Nanoobjects (UMR5248 CBMN); All. Geoffroy Saint-Hilaire 33600 Pessac, France; Phone: +33(0)540006848; christophe.cullin@u-bordeaux.fr Susan W. Liebman, Department of Pharmacology, University of Nevada, Reno, 1664 N Virginia, Mail stop 318, Reno, NV 89557; Phone: 847-710- 4830; sLiebman@unr.edu

Conflict of interest statement:

The authors declare no competing interests. The authors received no financial support for the research, authorship, and/or publication of this article.

Please cite this article as:

Mathilde Kadouch, Christelle Marchal, Sei- Kyoung Park, Sangeun Park, Sabine Castano, Susan W. Liebman and Christophe Cullin (

2026

). The p53 DNA-Binding (Core) Domain can form a prion that seeds prion formation in full-length p53.

Microbial Cell

13: 340-357. doi: 10.15698/mic2026.10.887

© 2026 Kadouch et al. This is an open-access article released under the terms of the Creative Commons Attribution (CC BY) license, which allows the unrestricted use, distribution, and reproduction in any medium, provided the original author and source are acknowledged.

Abstract:

The p53 tumor suppressor is frequently inactivated in human cancers, often through mutations in its core-domain. Here, we developed a yeast reporter system in S. cerevisiae to investigate whether the p53 core-domain can function as a prion-forming domain. By using a chimeric protein (CD-FDp) combining the p53 Core Domain and the Functional Domain of the yeast prion protein Ure2p, we demonstrate that inactive CD-FDp forms heritable, self-propagating aggregates. These aggregates exhibit canonical prion properties, including dominance, non-Mendelian segregation, and cytoduction-mediated transmission. CD-FDp prionization is independent of canonical chaperones (Hsp104, Hsp70, Hsp90), distinguishing it from classical yeast prions. Prionized CD-FDp enhances the formation of amyloid-like foci in full-length p53-EYFP, as evidenced by Thioflavin T staining, and can transmit its prion state to full-length p53 via cytoplasmic transfer. This indicates that CD-FDp propagons can induce structural conversion of p53, supporting an autocatalytic aggregation model. Using a Luria-Delbrück fluctuation assay, we quantified the prionization propensity of wild-type and cancer-associated p53 core-domain mutants. While most mutants (e.g., R273H, R282W) showed inactivation frequencies similar to wild-type, the R175H mutant exhibited an í18-fold increase in prionization frequency, which correlates with its known aggregation propensity in human cancers. This yeast system thus provides a quantitative platform to assess the prion-like behavior of p53 mutants and screen for inhibitors of p53 inactivation. Our findings establish p53 core-domain as a novel, structurally distinct prion-forming domain and offer a powerful experimental framework for studying p53 inactivation mechanisms, with potential implications for cancer therapeutics.