Structural Biology of DNA Repair: Spatial Organisation of the Multicomponent Complexes of Non-Homologous End Joining.

Every time a human cell’s DNA snaps in two—which happens thousands of times a day—a repair crew called Non-Homologous End Joining (NHEJ) must glue the broken ends back together without scrambling the genetic code. This project will map the three-dimensional architecture of the key protein machines that perform that repair. The problem is that these protein complexes are transient and loosely assembled, making them extremely difficult to capture in atomic detail. Without that structural map, researchers cannot understand why some people’s repair systems fail—leading to immune deficiencies or cancer—nor can they design drugs that deliberately block NHEJ in tumour cells to make radiation therapy more effective. If the team succeeds, they will produce the first high-resolution picture of how Ku70/Ku80, DNA-PKcs, DNA ligase IV, XRCC4, and XLF physically arrange themselves around a broken DNA end. This is fundamental science—there is no immediate clinical product. But structural biology has repeatedly turned such molecular blueprints into drug targets: knowing the exact shape of a protein pocket is what allows chemists to design molecules that fit it. For patients with inherited NHEJ defects, and for combination cancer therapies that exploit repair vulnerabilities, that knowledge is the necessary first step.