In-frame germline TP53 variant impairs p53 oligomerization and predisposes to cancer

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Authors

VANIKOVA Lucie MACHACKOVA Eva NEMCOVA Barbora SOUKUPOVA Jana PETREZSELYOVA Silvia NOVAKOVA Klara ŽENATOVÁ Marcela PAVLOVÁ Šárka KLEIBLOVA Petra KLEIBL Zdenek FORETOVA Lenka MACUREK Libor

Year of publication 2025
Type Article in Periodical
Magazine / Source Nature Scientific Reports
MU Faculty or unit

Faculty of Medicine

Citation
web https://www.nature.com/articles/s41598-025-14684-8
Doi http://dx.doi.org/10.1038/s41598-025-14684-8
Keywords TP53; p53; Li Fraumeni syndrome; Cancer
Attached files
Description Germline loss-of-function variants in TP53 cause Li-Fraumeni syndrome (LFS) characterized by an early onset of various cancer types including sarcomas, adrenocortical carcinoma, and breast cancer. The most common are mutations in the DNA binding domain of p53, but alterations in the oligomerization domain also cause LFS with variable level of penetrance. Here we report identification of a novel germline in-frame deletion TP53 variant c.1015_1023del p.(E339_F341del) in a family with early-onset breast cancer and other malignancies. Using functional testing, we found that a short deletion in the oligomerization domain in the p.E339_F341del variant severely impaired transcriptional activity of p53 in human cells and in a yeast model. The loss of the transactivation activity was consistent with an observed defect in formation of p53 tetramers. Finally, we found that cells expressing the p.E339_F341del variant were insensitive to inhibition of MDM2 by nutlin-3 confirming the functional defect. We conclude that the in-frame germline c.1015_1023del TP53 variant encodes a transcriptionally inactive protein and promotes LFS with a high penetrant cancer phenotype.
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