Activation of the repair of DNA double strand breaks by non-homologous end joining in human BCR/ABL-expressing cells by imatinib mesylate
DNA double strand breaks (DSBs) are generated by many anticancer drugs. The main mechanisms involved in processing of these DNA lesions in humans are non-homologous end joining (NHEJ) and homologous recombination repair. Recently, we have shown that oncogenic tyrosine kinase BCR/ABL activates DSBs repair, which in turn may induce resistance to DNA damage agents used in anticancer therapy. To explain the potential role of BCR/ABL in DSB repair by NHEJ pathway we examined the ability of two different leukemia BCR/ABL-expressing cell lines K562 and BV173 to repair DNA lesions induced by radiomimetic drug bleomycin and DNA topoisomerase II inhibitors: etoposide and sobuzoxane. DNA lesions induced by sobuzoxane can be repaired by a NHEJ pathway which is dependent on catalytic subunit of protein kinase dependent on DNA (DNA-PKcs), whereas lesions induced by etoposide are repaired by two distinct NHEJ pathways, dependent on or independent of DNA-PKcs. Cells incubated with imatinib mesylate, a specific inhibitor of the BCR/ABL tyrosine kinase, displayed resistance to these DNA damaging agents associated with accelerated kinetics of DSBs repair as measured by the neutral comet assay and pulsed field gel electrophoresis. However, those cells repaired DSBs with a lower efficacy in an in vitro non-homologous end-joining assay. We suggest, that imatinib elevates the level of the key NHEJ protein DNA-PKcs by blocking its proteasome-dependent degradation activated in BCR/ABL-positive cells and in consequence activates DSBs repair by DNA-PK-dependent NHEJ pathway, which can lead to the down-regulation of backup, DNA-PK-independent NHEJ.
This work was supported by grant KBN 3 P04A 032 25.