info:eu-repo/semantics/article
Compromised nuclear envelope integrity drives TREX1-dependent DNA damage and tumor cell invasion
Fecha
2021-09-21Registro en:
Nader, Guilherme Pedreira de Freitas; Agüera Gonzalez, Sonia; Routet, Fiona; Gratia, Matthieu; Maurin, Mathieu; et al.; Compromised nuclear envelope integrity drives TREX1-dependent DNA damage and tumor cell invasion; Cell Press; Cell; 184; 20; 21-9-2021; 5230-5246
0092-8674
1097-4172
CONICET Digital
CONICET
Autor
Nader, Guilherme Pedreira de Freitas
Agüera Gonzalez, Sonia
Routet, Fiona
Gratia, Matthieu
Maurin, Mathieu
Cancila, Valeria
Cadart, Clotilde
Palamidessi, Andrea
Ramos, Rodrigo Nalio
San Roman, Mabel
Gentili, Matteo
Yamada, Ayako
Williart, Alice
Lodillinsky, Catalina
Lagoutte, Emilie
Villard, Catherine
Viovy, Jean Louis
Tripodo, Claudio
Galon, Jérôme
Scita, Giorgio
Manel, Nicolas
Chavrier, Philippe
Piel, Matthieu
Resumen
Although mutations leading to a compromised nuclear envelope cause diseases such as muscular dystrophies or accelerated aging, the consequences of mechanically induced nuclear envelope ruptures are less known. Here, we show that nuclear envelope ruptures induce DNA damage that promotes senescence in non-transformed cells and induces an invasive phenotype in human breast cancer cells. We find that the endoplasmic reticulum (ER)-associated exonuclease TREX1 translocates into the nucleus after nuclear envelope rupture and is required to induce DNA damage. Inside the mammary duct, cellular crowding leads to nuclear envelope ruptures that generate TREX1-dependent DNA damage, thereby driving the progression of in situ carcinoma to the invasive stage. DNA damage and nuclear envelope rupture markers were also enriched at the invasive edge of human tumors. We propose that DNA damage in mechanically challenged nuclei could affect the pathophysiology of crowded tissues by modulating proliferation and extracellular matrix degradation of normal and transformed cells.