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.

尽管导致核膜受损的突变会导致肌肉营养不良或加速衰老等疾病，但机械诱导的核膜破裂的后果却鲜为人知。在这里，我们表明核膜破裂会诱导 DNA 损伤，从而促进非转化细胞的衰老，并在人类乳腺癌细胞中诱导侵袭性表型。我们发现内质网 (ER) 相关的核酸外切酶 TREX1 在核膜破裂后易位到细胞核中，并且是诱导 DNA 损伤所必需的。在乳腺导管内，细胞拥挤导致核膜破裂，产生 TREX1 依赖性 DNA 损伤，从而推动原位进展癌至浸润期。DNA 损伤和核膜破裂标志物也在人类肿瘤的侵袭边缘富集。我们提出机械损伤细胞核中的 DNA 损伤可通过调节正常和转化细胞的增殖和细胞外基质降解来影响拥挤组织的病理生理学。