Figure 4: Resolution of damaged termini in NHEJ. Ku binds to DNA ends and recruits DNA-PKcs, the XRCC4/DNA ligase IV complex, and XLF. Synapsis of two DSB ends triggers DNA-PKcs autophosphorylation in trans, inducing a conformational change that allows gap filling by polymerase λ and finally ligation by DNA ligase IV. Removal of 5′- and 3′-terminal blocks by end processing enzymes can potentially occur at several steps in the pathway: before recruitment of any NHEJ factors (1); after recruitment of Ku (2) (e.g., by Ku itself [18]); or after DNA-PKcs autophosphorylation (3), which increases accessibility of the ends. In addition, processing of terminal blocks in the second strand can occur after ligation of the first strand (4), possibly by SSB repair pathways after dissociation of NHEJ proteins.