The Werner syndrome ATP-dependent helicase (WRN helicase) is unusual among RecQ DNA family helicases in having an additional exonuclease activity. WRN interacts with DNA-PKcs and the Ku protein complex. This observation, combined with evidence that WRN deficient cells produce extensive deletions at sites of joining of non-homologous DNA ends, suggests a role for WRN protein in the DNA repair process of non-homologous end joining (NHEJ). WRN also physically interacts with the major NHEJ factor X4L4 (XRCC4-DNA ligase 4 complex). X4L4 stimulates WRN exonuclease activity that likely facilitates DNA end processing prior to final ligation by X4L4.