法国图卢兹大学Gaëlle Legube团队近期取得重要工作进展，他们研究探讨了染色质区室化调节对DNA损伤的应答反应。相关研究成果2023年10月18日在线发表于《自然》杂志上。

据介绍，DNA损伤反应对保护基因组完整性至关重要。尽管染色质在DNA修复中的作用已经被研究过，但染色体折叠对这些过程的作用仍不清楚。

研究人员报道，在哺乳动物细胞中产生双链断裂（DSB）后，ATM通过聚集由γH2AX和53BP1修饰过的受损拓扑相关结构域来驱动新染色质隔室（D隔室）的形成。该隔室通过与聚合物-聚合物相分离而非液-液相分离一致的机制形成。D区主要出现在G1期，独立于粘着蛋白，并在DNA依赖性蛋白激酶（DNA-PK）或R-环积累的药理学抑制后增强。重要的是，富含R环的DNA损伤反应基因在物理上定位于D区室，这有助于它们的最佳激活，为DNA损伤反应中的DSB聚类提供功能。然而，DSB诱导的染色体重组是以增加易位率为代价的，这也在癌症基因组中观察到。

总的来说，研究人员描述了DSB诱导的区室化如何协调DNA损伤修复反应，并强调了染色体结构在基因组不稳定性中的关键影响。

附：英文原文

Title: Chromatin compartmentalization regulates the response to DNA damage

Author: Arnould, Coline, Rocher, Vincent, Saur, Florian, Bader, Aldo S., Muzzopappa, Fernando, Collins, Sarah, Lesage, Emma, Le Bozec, Benjamin, Puget, Nadine, Clouaire, Thomas, Mangeat, Thomas, Mourad, Raphael, Ahituv, Nadav, Noordermeer, Daan, Erdel, Fabian, Bushell, Martin, Marnef, Aline, Legube, Galle

Issue&Volume: 2023-10-18

Abstract: The DNA damage response is essential to safeguard genome integrity. Although the contribution of chromatin in DNA repair has been investigated1,2, the contribution of chromosome folding to these processes remains unclear3. Here we report that, after the production of double-stranded breaks (DSBs) in mammalian cells, ATM drives the formation of a new chromatin compartment (D compartment) through the clustering of damaged topologically associating domains, decorated with γH2AX and 53BP1. This compartment forms by a mechanism that is consistent with polymer–polymer phase separation rather than liquid–liquid phase separation. The D compartment arises mostly in G1 phase, is independent of cohesin and is enhanced after pharmacological inhibition of DNA-dependent protein kinase (DNA-PK) or R-loop accumulation. Importantly, R-loop-enriched DNA-damage-responsive genes physically localize to the D compartment, and this contributes to their optimal activation, providing a function for DSB clustering in the DNA damage response. However, DSB-induced chromosome reorganization comes at the expense of an increased rate of translocations, also observed in cancer genomes. Overall, we characterize how DSB-induced compartmentalization orchestrates the DNA damage response and highlight the critical impact of chromosome architecture in genomic instability.

DOI: 10.1038/s41586-023-06635-y

Source: https://www.nature.com/articles/s41586-023-06635-y