Crystal structure of the Xrcc4 DNA repair protein and implications for endjoining

XRCC4 is essential for carrying out non-homologous DNA end joining (NHEJ) i n all eukaryotes and, in particular, V(D)J recombination in vertebrates. Xr cc4 protein forms a complex with DNA ligase IV that rejoins two DNA ends in the last step of V(D)J recombination and NHEJ to repair double strand brea ks. XRCC4-defective cells are extremely sensitive to ionizing radiation, an d disruption of the XRCC4 gene results in embryonic lethality in mice. Here we report the crystal structure of a functional fragment of Xrcc4 at 2.7 A resolution. Xrcc4 protein forms a strikingly elongated dumb-bell-like tetr amer. Each of the N-terminal globular head domains consists of a beta -sand wich and a potentially DNA-binding helix-turn-helix motif. The C-terminal s talk comprising a single alpha -helix >120 Angstrom in length is partly inc orporated into a four-helix bundle in the Xrcc4 tetramer and partly involve d in interacting with ligase IV. The Xrcc4 structure suggests a possible mo de of coupling. ligase IV association with DNA binding for effective ligati on of DNA ends.