Structure of XLF-XRCC4 Provides Model for Double Strand Break Repair

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](http://www.ncbi.nlm.nih.gov/pubmed/21775435), 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.