Dynamic assemblies and coordinated reactions of non-homologous end joining

Lan Liu, Jun Li, Metztli Cisneros-Aguirre, Arianna Merkell, Jeremy M. Stark, Martin Gellert () and Wei Yang ()
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Lan Liu: NIDDK, National Institutes of Health
Jun Li: NIDDK, National Institutes of Health
Metztli Cisneros-Aguirre: Beckman Research Institute of the City of Hope
Arianna Merkell: Beckman Research Institute of the City of Hope
Jeremy M. Stark: Beckman Research Institute of the City of Hope
Martin Gellert: NIDDK, National Institutes of Health
Wei Yang: NIDDK, National Institutes of Health

Nature, 2025, vol. 643, issue 8072, 847-854

Abstract: 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 polymerase μ 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.

Date: 2025
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DOI: 10.1038/s41586-025-09078-9

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