Université de Paris and Université Paris Saclay, INSERM, iRCM/IBFJ, CEA, UMR Stabilité Génétique, Cellules Souches et Radiations, F-92265 Fontenay-aux-Roses, France.
"DNA Repair and Ageing" Team, iRCM/IBFJ, DRF, CEA, France.
Sci Adv. 2021 Aug 27;7(35). doi: 10.1126/sciadv.abb3799. Print 2021 Aug.
Double-strand breaks (DSBs) are harmful lesions and a major cause of genome instability. Studies have suggested a link between the nuclear envelope and the DNA damage response. Here, we show that lamin B1, a major component of the nuclear envelope, interacts directly with 53BP1 protein, which plays a pivotal role in the DSB repair. This interaction is dissociated after DNA damage. Lamin B1 overexpression impedes 53BP1 recruitment to DNA damage sites and leads to a persistence of DNA damage, a defect in nonhomologous end joining and an increased sensitivity to DSBs. The identification of interactions domains between lamin B1 and 53BP1 allows us to demonstrate that the defect of 53BP1 recruitment and the DSB persistence upon lamin B1 overexpression are due to sequestration of 53BP1 by lamin B1. This study highlights lamin B1 as a factor controlling the recruitment of 53BP1 to DNA damage sites upon injury.
双链断裂（DSBs）是有害的损伤，也是基因组不稳定的主要原因。研究表明核膜与 DNA 损伤反应之间存在联系。在这里，我们显示核膜的主要成分之一核层蛋白 B1 与在 DSB 修复中起关键作用的 53BP1 蛋白直接相互作用。这种相互作用在 DNA 损伤后被分离。核层蛋白 B1 的过表达阻碍了 53BP1 向 DNA 损伤部位的募集，并导致 DNA 损伤的持续存在、非同源末端连接的缺陷和对 DSB 的敏感性增加。核层蛋白 B1 和 53BP1 之间相互作用区域的鉴定使我们能够证明，在核层蛋白 B1 过表达时，53BP1 的募集缺陷和 DSB 的持续存在是由于 53BP1 被核层蛋白 B1 隔离。这项研究强调了核层蛋白 B1 作为控制 53BP1 在损伤时募集到 DNA 损伤部位的一个因素。
