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核被膜完整性受损驱动TREX1依赖性DNA损伤和肿瘤细胞侵袭
作者:小柯机器人 发布时间:2021/9/24 13:40:56

法国PSL研究型大学Matthieu Piel等研究人员合作发现,核被膜完整性受损驱动TREX1依赖性DNA损伤和肿瘤细胞侵袭。相关论文于2021年9月21日在线发表在《细胞》杂志上。

研究人员发现,核被膜破裂会诱发DNA损伤,促进非转化细胞的衰老,并诱发人类乳腺癌细胞的侵入性表型。研究人员发现,内质网(ER)相关的外切酶TREX1在核包膜破裂后转入细胞核,并且是诱导DNA损伤所需的。在乳腺管内,细胞拥挤导致核被膜破裂,产生TREX1依赖性的DNA损伤,从而推动原位癌向浸润期发展。DNA损伤和核被膜破裂标志物也在人类肿瘤的侵袭边缘富集。

研究人员提出,受到机械压力的细胞核中的DNA损伤可能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。

据介绍,尽管导致核被膜受损的突变会导致疾病,如肌肉萎缩症或加速衰老,但机械诱导的核被膜破裂的后果却不为人所知。

附:英文原文

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

Author: Guilherme Pedreira de Freitas Nader, Sonia Agüera-Gonzalez, Fiona Routet, Matthieu Gratia, Mathieu Maurin, Valeria Cancila, Clotilde Cadart, Andrea Palamidessi, Rodrigo Nalio Ramos, Mabel San Roman, Matteo Gentili, Ayako Yamada, Alice Williart, Catalina Lodillinsky, Emilie Lagoutte, Catherine Villard, Jean-Louis Viovy, Claudio Tripodo, Jérme Galon, Giorgio Scita, Nicolas Manel, Philippe Chavrier, Matthieu Piel

Issue&Volume: 2021-09-21

Abstract: Although mutations leading to a compromised nuclear envelope cause diseases such asmuscular dystrophies or accelerated aging, the consequences of mechanically inducednuclear envelope ruptures are less known. Here, we show that nuclear envelope rupturesinduce DNA damage that promotes senescence in non-transformed cells and induces aninvasive phenotype in human breast cancer cells. We find that the endoplasmic reticulum(ER)-associated exonuclease TREX1 translocates into the nucleus after nuclear enveloperupture and is required to induce DNA damage. Inside the mammary duct, cellular crowdingleads to nuclear envelope ruptures that generate TREX1-dependent DNA damage, therebydriving the progression of in situ carcinoma to the invasive stage. DNA damage and nuclear envelope rupture markerswere also enriched at the invasive edge of human tumors. We propose that DNA damagein mechanically challenged nuclei could affect the pathophysiology of crowded tissuesby modulating proliferation and extracellular matrix degradation of normal and transformed cells.

DOI: 10.1016/j.cell.2021.08.035

Source: https://www.cell.com/cell/fulltext/S0092-8674(21)01046-1

期刊信息
Cell:《细胞》,创刊于1974年。隶属于细胞出版社,最新IF:36.216
官方网址:https://www.cell.com/