The oncogenic fusion protein TAZ::CAMTA1 promotes genomic instability and senescence through hypertranscription.
Commun Biol
; 6(1): 1174, 2023 11 18.
Article
em En
| MEDLINE
| ID: mdl-37980390
ABSTRACT
TAZCAMTA1 is a fusion protein found in over 90% of Epithelioid Hemangioendothelioma (EHE), a rare vascular sarcoma with an unpredictable disease course. To date, how TAZCAMTA1 initiates tumour formation remains unexplained. To study the oncogenic mechanism leading to EHE initiation, we developed a model system whereby TAZCAMTA1 expression is induced by doxycycline in primary endothelial cells. Using this model, we establish that upon TAZCAMTA1 expression endothelial cells rapidly enter a hypertranscription state, triggering considerable DNA damage. As a result, TC-expressing cells become trapped in S phase. Additionally, TAZCAMTA1-expressing endothelial cells have impaired homologous recombination, as shown by reduced BRCA1 and RAD51 foci formation. Consequently, the DNA damage remains unrepaired and TAZCAMTA1-expressing cells enter senescence. Knockout of Cdkn2a, the most common secondary mutation found in EHE, allows senescence bypass and uncontrolled growth. Together, this provides a mechanistic explanation for the clinical course of EHE and offers novel insight into therapeutic options.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Transativadores
/
Hemangioendotelioma Epitelioide
Limite:
Humans
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article