Results tagged “XRCC4,” from The SIBYLS Beamline

DNA double strand break repair via nonhomologous end joining is a critical regulatory function that maintains genomic integrity. One of the major factors involved in this process is the XLF-XRCC4 protein complex. Although mutation of either XLF or XRCC4 leads to defects in break repair, the function of the XLF-XRCC4 complex has remained enigmatic. In their Paper of the Week, Hammel et al. used structure-based methods to elucidate the mechanism by which XLF-XRCC4 promotes double strand break repair. The authors solved the crystal structure of the XLF-XRCC4 complex using the N-terminal head domains of each protein and identified two key structural features that stabilize the complex: a key-lock interaction that links the two proteins and a set of hydrogen-bonding interactions that supplement the key-lock bond. Furthermore, the authors found that the C-terminal domain of XLF was crucial for promoting the formation and extension of filaments of the XLF-XRCC4 complex, allowing for interaction with DNA in a concentration-dependent manner. The crystal structure also identified a putative DNA-binding region, located at the XLF-XRCC4 interface, which was confirmed through addition of DNA oligomers. Subsequent addition of the break repair complex nucleator Ku and DNA ligase IV allowed the authors to develop a model for nonhomologous end joining in which Ku initially binds the damaged DNA site and recruits the XLF-XRCC4 complex, which is necessary for proper alignment of damaged DNA for repair by DNA ligase IV. Importantly, the elucidation of the structure of the XLF-XRCC4 scaffold provides potential targets for anticancer therapeutics.