美国国立卫生研究院杨薇研究团队近日取得一项新成果。经过不懈努力，他们的研究认为非同源末端连接的动态组装与配位反应。该项研究成果发表在2025年6月11日出版的《自然》上。

在这里，该课题组报道了NHEJ最后步骤的重构和DNA聚合酶的结构μ和连接酶IV （LIG4）参与间隙填充和末端连接。这些反应发生在由XRCC4和XLF组成的柔性ω形框架中。两个断裂的DNA末端，每一个都被Ku70-Ku80内部包围，由LIG4介导，停靠在ω框架上。每条ω臂上的DNA聚合酶和连接酶只能修复一条具有特定极性的断裂链；NHEJ的最后步骤需要一对这样的酶的协调和切换。助剂XLF和PAXX加性刺激NHEJ反应。作为DNA末端传感器和保护器，LIG4取代DNA- pkcs进行末端连接，并在两个DNA末端架起桥梁，供聚合酶填补剩余空隙。这些组装为NHEJ抑制提供了新的靶点，以提高放疗的疗效和基因编辑的准确性。

据了解，非同源末端连接（Non-homologothem end joining， NHEJ）是高等真核生物双链DNA断裂的主要修复途径。

附：英文原文

Title: Dynamic assemblies and coordinated reactions of non-homologous end joining

Author: Liu, Lan, Li, Jun, Cisneros-Aguirre, Metztli, Merkell, Arianna, Stark, Jeremy M., Gellert, Martin, Yang, Wei

Issue&Volume: 2025-06-11

Abstract: Non-homologous end joining (NHEJ) is the main repair pathway of double-strand DNA breaks in higher eukaryotes1,2. Here we report reconstitution of the final steps of NHEJ and structures of DNA polymeraseμ and ligase IV (LIG4) engaged in gap filling and end joining. These reactions take place in a flexible ω-shaped framework composed of XRCC4 and XLF. Two broken DNA ends, each encircled by Ku70–Ku80 internally, are docked onto the ω frame, mediated by LIG4. DNA polymerase and ligase attached to each ω arm repair only one broken strand of a defined polarity; the final steps of NHEJ requires coordination and toggling of a pair of such enzymes. The facilitators XLF and PAXX additively stimulate NHEJ reactions. As DNA-end sensor and protector, LIG4 replaces DNA-PKcs for end joining and bridges the two DNA ends for polymerase to fill remaining gaps. These assemblies present new targets for NHEJ inhibition to enhance efficacy of radiotherapy and accuracy of gene editing.

DOI: 10.1038/s41586-025-09078-9

Source: https://www.nature.com/articles/s41586-025-09078-9