近日，丹麦哥本哈根大学Jiri Lukas和英国牛津大学Lothar Schermelleh等研究人员合作揭示，染色质拓扑结构的稳定保证了基因组的完整性。2019年10月24日，国际知名学术期刊《自然》发表了这一成果。

研究人员使用超分辨率显微镜显示53BP1和RIF1形成了一个自主的功能模块，其可稳定DNA断裂部位的三维染色质拓扑。此过程是通过将53BP1累积在紧密染色质的与拓扑相关域（TAD）序列共定位的区域中起始的，然后将RIF1募集到这些域之间的边界。53BP1和RIF1的交替分布将单个DNA双链断裂（DSB）位点上几个相邻的TAD大小的结构稳定为有序的圆形排列。敲除53BP1或RIF1（而不是保护蛋白）会破坏这种排列方式，并导致DSB两边染色质失活、染色质间空间减少、DNA修复蛋白异常扩散以及DNA末端过度切除。cohesin蛋白的敲除会触发类似的拓扑畸变，这体现了DNA断裂后染色质结构的维持涉及塑造三维核组织的基本机制。

由于DSB两侧染色质的拓扑稳定与DNA修复无关，因此研究人员认为，除了提供结构支架以保护DNA末端免受异常加工之外，53BP1和RIF1还可以保护被DNA断裂所破坏的基因座的表观遗传完整性。

据介绍，为了保护DSB时基因组完整性，哺乳动物细胞动员相邻的染色质来保护DNA末端免受过度切除，这可能破坏修复保真度并损害健康染色体。53BP1负责这种形式的基因组监视，其在DSB处的积累触发了RIF1和shieldin-CST-POLα复合物的依次募集。这种途径如何反映和影响三维核结构尚不清楚。

附：英文原文

Title: Stabilization of chromatin topology safeguards genome integrity

Author: Fena Ochs, Gopal Karemore, Ezequiel Miron, Jill Brown, Hana Sedlackova, Maj-Britt Rask, Marko Lampe, Veronica Buckle, Lothar Schermelleh, Jiri Lukas, Claudia Lukas

Issue&Volume: 2019-10-23

Abstract: To safeguard genome integrity in response to DNA double-strand breaks (DSBs), mammalian cells mobilize the neighbouring chromatin to shield DNA ends against excessive resection that could undermine repair fidelity and cause damage to healthy chromosomes1. This form of genome surveillance is orchestrated by 53BP1, whose accumulation at DSBs triggers sequential recruitment of RIF1 and the shieldin–CST–POLα complex2. How this pathway reflects and influences the three-dimensional nuclear architecture is not known. Here we use super-resolution microscopy to show that 53BP1 and RIF1 form an autonomous functional module that stabilizes three-dimensional chromatin topology at sites of DNA breakage. This process is initiated by accumulation of 53BP1 at regions of compact chromatin that colocalize with topologically associating domain (TAD) sequences, followed by recruitment of RIF1 to the boundaries between such domains. The alternating distribution of 53BP1 and RIF1 stabilizes several neighbouring TAD-sized structures at a single DBS site into an ordered, circular arrangement. Depletion of 53BP1 or RIF1 (but not shieldin) disrupts this arrangement and leads to decompaction of DSB-flanking chromatin, reduction in interchromatin space, aberrant spreading of DNA repair proteins, and hyper-resection of DNA ends. Similar topological distortions are triggered by depletion of cohesin, which suggests that the maintenance of chromatin structure after DNA breakage involves basic mechanisms that shape three-dimensional nuclear organization. As topological stabilization of DSB-flanking chromatin is independent of DNA repair, we propose that, besides providing a structural scaffold to protect DNA ends against aberrant processing, 53BP1 and RIF1 safeguard epigenetic integrity at loci that are disrupted by DNA breakage.

DOI: 10.1038/s41586-019-1659-4

Source: https://www.nature.com/articles/s41586-019-1659-4