Abstract
The mammalian non-homologous end joining (NHEJ) is required for class switch and V(D)J recombination as well as repairing DNA double-strand breaks (DSBs). Initiated by the binding of Ku70/Ku80 (Ku) dimer to DNA ends and the recruitment of the DNA-dependent protein kinase catalytic subunit, NHEJ plays a key role in DSB repair. While the overall function of Ku70 in NHEJ is well documented, the specific role of its highly conserved C-terminal SAP (SAF-A/B, Acinus, and PIAS) domain remains elusive. In this study, we developed a novel mouse model by deleting the SAP domain but preserving Ku70 nuclear localization and its dimerization ability with Ku80. We found that Ku70 SAP deletion (ΔSAP) had little effect on class switch and V(D)J recombination or animal development but sensitized the animals and cells to radiation and chemotherapy agents. Ku70-ΔSAP cells exhibited reduced Ku70 recruitment and dampened DNA ligase IV retention to DNA damage sites after radiation exposure and displayed a spreading pattern of DSB marker γH2AX after DNA damage. Our findings suggest that the SAP domain is required for cells to optimally cope with DNA damage, making it a potential target to modulate cell sensitivity to therapeutic DSB-inducing agents without interfering with the developmental function of Ku70.