Up-regulation of WRN and DNA ligase IIIα in chronic myeloid leukernia:: consequences for the repair of DNA double-strand breaks

Expression of oncogenic BCR-ABL in chronic myeloid leukemia (CML) results in increased reactive oxygen species (ROS) that in turn cause increased DNA damage, including DNA double-strand breaks (DSBs). We have previously shown increased error-prone repair of DSBs by nonhomologous end-joining (NHEJ) in CML cells. Recent reports have identified alternative NHEJ pathways that are highly error prone, prompting us to examine the role of the alternative NHEJ pathways in BCR-ABL-positive CML. Importantly, we show that key proteins in the major NHEJ pathway, Artemis and DNA ligase IV, are down-regulated, whereas DNA ligase III alpha, and the protein deleted in Werner syndrome, WRN, are up-regulated. DNA ligase III alpha and WRN form a complex that is recruited to DSBs in CML cells. Furthermore, knockdown of either DNA ligase 116 or WRN leads to increased accumulation of unrepaired DSBs, demonstrating that they contribute to the repair of DSBs. These results indicate that altered DSB repair in CML cells is caused by the increased activity of an alternative NHEJ repair pathway, involving DNA ligase III alpha and WRN. We suggest that, although the repair of ROS-incluced DSBs by this pathway contributes to the survival of CML cells, the resultant genomic instability drives disease progression.