WRN counteracts the NHEJ pathway upon camptothecin exposure

We investigated the function of the interaction between WRN (Werner syndrome gene product) and Ku70 and between WRN and DNA-PKcs, which are components of the DNA-PKcs/Ku70/Ku80 complex, by generating KU70−/−/WRN−/− and DNA-PKcs−/−/−/WRN−/− double-gene knockout chicken DT40 cells. When treated with camptothecin (CPT), an inhibitor of DNA topoisomerase I, WRN−/− cells showed higher sensitivity than wild-type cells, whereas KU70−/− and DNA-PKcs−/−/− cells showed hyper-resistance. Disruption of KU70 or DNA-PKcs suppressed the sensitivity of WRN−/− cells to CPT, rendering them as resistant to CPT treatment as KU70−/− and DNA-PKcs−/−/− cells. On the other hand, CPT sensitivity of BLM−/− cells, which are defective in a RecQ helicase similar to WRN, was enhanced by deletion of KU70. The implications for the function of WRN in the non-homologous end-joining pathway of DNA repair involving Ku70 and DNA-PKcs, which may be the cause of lethality in the presence of CPT, will be discussed.