Compromised nuclear envelope integrity drives TREX1-dependent DNA damage and tumor cell invasion

Guilherme Pedreira de Freitas Nader (1) , Sonia Agüera-Gonzalez (1) , Fiona Routet (1) , Matthieu Gratia (1) , Mathieu Maurin (1) , Valeria Cancila (2) , Clotilde Cadart (3) , Andrea Palamidessi (4) , Rodrigo Nalio Ramos (5) , Mabel San (1) , Matteo Gentili (6) , Ayako Yamada (7) , Alice Williart (1) , Catalina Lodillinsky (8) , Emilie Lagoutte (1) , Catherine Villard (1) , Jean-Louis Viovy (1) , Claudio Tripodo (2) , Jérôme Galon (5) , Giorgio Scita (4) , Nicolas Manel (1) , Philippe Chavrier (1) , Matthieu Piel (1)

1 Centre de recherche de l'Institut Curie [Paris]
2 Università degli studi di Palermo - University of Palermo
3 UC - University of California
4 IFOM - IFOM, Istituto FIRC di Oncologia Molecolare
5 CRC (UMR_S_1138 / U1138) - Centre de Recherche des Cordeliers
6 MIT - Massachusetts Institute of Technology
7 ENS-PSL - École normale supérieure - Paris
8 CONICET - Consejo Nacional de Investigaciones Científicas y Técnicas [Buenos Aires]

While 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 which promotes senescence in non-transformed cells, and induces an invasive phenotype in human breast cancer cells. We find that the 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 which 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.

Domaines: Sciences du Vivant [q-bio]

Guilherme Pedreira de Freitas Nader, Sonia Agüera-Gonzalez, Fiona Routet, Matthieu Gratia, Mathieu Maurin, et al.. Compromised nuclear envelope integrity drives TREX1-dependent DNA damage and tumor cell invasion. Cell, 2021, ⟨10.1016/j.cell.2021.08.035⟩. ⟨hal-03392287⟩