EXO1 is associated with Ku-independent DNA double strand break repair pathway and the inhibition of EXO1 chemosensitizes DDP resistance lung cancer cells

Alternative end joining (Alt-EJ) is an error-prone repair pathway of DNA double-strand break (DSB) which functions independent of nonhomologous end joining (NHEJ) core factors, especially Ku protein. As a less studied repair pathway, but not less important one, its involving proteins need further investigation. By using single-stranded DNA oligomers (ssO) displacing Ku protein from damaged DNA ends and facilitating Ku independent DSB repair proteins recruited to DNA ends, we identify EXO1 exonuclease is associated with Alt-EJ and may consider as a novel player participating in Alt-EJ pathway in Ku70-deficient lung cancer cells. Depletion of EXO1 greatly increased cellular sensitivity to Cisplatin (DDP) and DNA-dependent protein kinase (DNA-PK) inhibitor NU7026 in vitro due to the inhibition of the repair of DSBs. EXO1 inhibition also attenuated the growth of DPP-resistant tumors in the in vivo mouse model through increasing expression of apoptotic protein caspase-3 and 53BP1. Our results revealed EXO1 participation in DSB repair by Alt-EJ. Suppression of EXO1 provides a chemosensitizing therapeutic option for lung cancer patients of DDP resistance.