Dynamic assemblies and coordinated reactions of non-homologous end joining

• 成果类型: Article
• 署名作者: Liu, Lan; Li, Jun; Cisneros-Aguirre, Metztli; Merkell, Arianna; Stark, Jeremy M.; Gellert, Martin; Yang, Wei
• 署名单位: National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK); City of Hope; Beckman Research Institute of City of Hope
• 刊物名称: Nature
• ISSN/ISSBN: 0028-1054
• DOI: 10.1038/s41586-025-09078-9
• 发表日期: 2025-07-17
• 关键词: dna-ligase iv; structural basis; brct domain; crystal-structure; repair protein; xrcc4 protein; xlf; complex; paxx; interacts

摘要

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 polymerase mu and ligase IV (LIG4) engaged in gap filling and end joining. These reactions take place in a flexible omega-shaped framework composed of XRCC4 and XLF. Two broken DNA ends, each encircled by Ku70-Ku80 internally, are docked onto the omega frame, mediated by LIG4. DNA polymerase and ligase attached to each omega 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.