Up-regulation of WRN and DNA ligase IIIalpha in chronic myeloid leukemia: consequences for the repair of DNA double-strand breaks.

Abstract	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 IIIalpha, and the protein deleted in Werner syndrome, WRN, are up-regulated. DNA ligase IIIalpha and WRN form a complex that is recruited to DSBs in CML cells. Furthermore, "knockdown" of either DNA ligase IIIalpha 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 IIIalpha and WRN. We suggest that, although the repair of ROS-induced DSBs by this pathway contributes to the survival of CML cells, the resultant genomic instability drives disease progression.
Authors	Annahita Sallmyr, Alan E Tomkinson, Feyruz V Rassool
Journal	Blood (Blood) Vol. 112 Issue 4 Pg. 1413-23 (Aug 15 2008) ISSN: 1528-0020 [Electronic] United States
PMID	18524993 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References	DNA-Binding Proteins LIG4 protein, human Nuclear Proteins Poly-ADP-Ribose Binding Proteins Xenopus Proteins DCLRE1C protein, human Endonucleases Exodeoxyribonucleases RecQ Helicases WRN protein, human Werner Syndrome Helicase DNA Ligases DNA Ligase ATP DNA ligase III alpha protein, Xenopus
Topics	Cell Survival DNA Breaks, Double-Stranded DNA Ligase ATP DNA Ligases (analysis, physiology) DNA Repair DNA-Binding Proteins Disease Progression Endonucleases Exodeoxyribonucleases (analysis, physiology) Genomic Instability Humans Leukemia, Myelogenous, Chronic, BCR-ABL Positive (genetics, pathology) Nuclear Proteins Poly-ADP-Ribose Binding Proteins RecQ Helicases (analysis, physiology) Up-Regulation Werner Syndrome Helicase Xenopus Proteins

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