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

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00209805%3A_____%2F25%3A00080386" target="_blank" >RIV/00209805:_____/25:00080386 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/68378050:_____/25:00638564 RIV/00216224:14110/25:00141890 RIV/00216208:11110/25:10501192 RIV/65269705:_____/25:00082605 RIV/00064165:_____/25:10501192

Výsledek na webu

<a href="https://www.nature.com/articles/s41598-025-14684-8" target="_blank" >https://www.nature.com/articles/s41598-025-14684-8</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1038/s41598-025-14684-8" target="_blank" >10.1038/s41598-025-14684-8</a>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

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

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30204 - Oncology

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2025

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Scientific reports

ISSN

2045-2322

e-ISSN

2045-2322

Svazek periodika

15

Číslo periodika v rámci svazku

1

Stát vydavatele periodika

DE - Spolková republika Německo

Počet stran výsledku

9

Strana od-do

30459

Kód UT WoS článku

001554398700042

EID výsledku v databázi Scopus

2-s2.0-105013639845