小柯机器人

法国国家科学研究中心Gaëlle Legube团队发现，环挤压是DNA损伤修复灶形成的机制。这一研究成果于2021年2月17日在线发表在国际学术期刊《自然》上。

据研究人员介绍，DNA双链断裂（DSB）的修复对于维护基因组完整性至关重要。当形成DSB时，PI3K相关的ATM激酶迅速触发兆碱基大小的染色质结构域的建立并通过磷酸化组蛋白H2AX（γH2AX）来修饰，该结构域充当形成DNA损伤反应灶的种子。目前尚不清楚这些灶点如何快速组装从而在细胞核内建立“易于修复”的环境。拓扑关联结构域是3D基因组组织的一个关键特征，它使转录和复制区分开来，但对其DNA修复过程的贡献知之甚少。

研究人员发现，拓扑关联结构域是DNA损伤反应的功能单元，并且有助于以正确的方式建立γH2AX–53BP1染色质域，其方式包括在DSB的两侧进行单侧cohesin蛋白介导的环挤出。研究提出了一个模型，其中含H2AX的核小体主动通过DSB锚定的cohesin时会迅速磷酸化。这项工作强调了染色体构象在维持基因组完整性中的重要性，并证明了通过环挤压法建立染色质修饰。 

附：英文原文

Title: Loop extrusion as a mechanism for formation of DNA damage repair foci

Author: Coline Arnould, Vincent Rocher, Anne-Laure Finoux, Thomas Clouaire, Kevin Li, Felix Zhou, Pierre Caron, Philippe. E. Mangeot, Emiliano P. Ricci, Raphal Mourad, James E. Haber, Daan Noordermeer, Galle Legube

Issue&Volume: 2021-02-17

Abstract: The repair of DNA double-strand breaks (DSBs) is essential for safeguarding genome integrity. When a DSB forms, the PI3K-related ATM kinase rapidly triggers the establishment of megabase-sized, chromatin domains decorated with phosphorylated histone H2AX (γH2AX), which act as seeds for the formation of DNA-damage response foci1. It is unclear how these foci are rapidly assembled to establish a ‘repair-prone’ environment within the nucleus. Topologically associating domains are a key feature of 3D genome organization that compartmentalize transcription and replication, but little is known about their contribution to DNA repair processes2,3. Here we show that topologically associating domains are functional units of the DNA damage response, and are instrumental for the correct establishment of γH2AX–53BP1 chromatin domains in a manner that involves one-sided cohesin-mediated loop extrusion on both sides of the DSB. We propose a model in which H2AX-containing nucleosomes are rapidly phosphorylated as they actively pass by DSB-anchored cohesin. Our work highlights the importance of chromosome conformation in the maintenance of genome integrity and demonstrates the establishment of a chromatin modification by loop extrusion.

DOI: 10.1038/s41586-021-03193-z

Source: https://www.nature.com/articles/s41586-021-03193-z

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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