BCR/ABL Stimulates WRN to Promote Survival and Genomic Instability
- 1 February 2011
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 71 (3), 842-851
- https://doi.org/10.1158/0008-5472.can-10-1066
Abstract
BCR/ABL-transformed chronic myeloid leukemia (CML) cells accumulate numerous DNA double-strand breaks (DSB) induced by reactive oxygen species (ROS) and genotoxic agents. To repair these lesions BCR/ABL stimulate unfaithful DSB repair pathways, homologous recombination repair (HRR), nonhomologous end-joining (NHEJ), and single-strand annealing (SSA). Here, we show that BCR/ABL enhances the expression and increase nuclear localization of WRN (mutated in Werner syndrome), which is required for processing DSB ends during the repair. Other fusion tyrosine kinases (FTK), such as TEL/ABL, TEL/JAK2, TEL/PDGFβR, and NPM/ALK also elevate WRN. BCR/ABL induces WRN mRNA and protein expression in part by c-MYC-mediated activation of transcription and Bcl-xL–dependent inhibition of caspase-dependent cleavage, respectively. WRN is in complex with BCR/ABL resulting in WRN tyrosine phosphorylation and stimulation of its helicase and exonuclease activities. Activated WRN protects BCR/ABL-positive cells from the lethal effect of oxidative and genotoxic stresses, which causes DSBs. In addition, WRN promotes unfaithful recombination-dependent repair mechanisms HRR and SSA, and enhances the loss of DNA bases during NHEJ in leukemia cells. In summary, we postulate that BCR/ABL-mediated stimulation of WRN modulates the efficiency and fidelity of major DSB repair mechanisms to protect leukemia cells from apoptosis and to facilitate genomic instability. Cancer Res; 71(3); 842–51. ©2010 AACR.Keywords
Other Versions
This publication has 52 references indexed in Scilit:
- Chronic myeloid leukemia: mechanisms of blastic transformationJCI Insight, 2010
- Exonuclease Function of Human Mre11 Promotes Deletional Nonhomologous End JoiningJournal of Biological Chemistry, 2009
- BCR-ABL promotes the frequency of mutagenic single-strand annealing DNA repairPublished by American Society of Hematology ,2009
- Rising from the RecQ-age: the role of human RecQ helicases in genome maintenanceTrends in Biochemical Sciences, 2008
- BCR/ABL and Other Kinases from Chronic Myeloproliferative Disorders Stimulate Single-Strand Annealing, an Unfaithful DNA Double-Strand Break RepairCancer Research, 2008
- Up-regulation of WRN and DNA ligase IIIα in chronic myeloid leukemia: consequences for the repair of DNA double-strand breaksBlood, 2008
- Werner Protein Cooperates with the XRCC4-DNA Ligase IV Complex in End-ProcessingBiochemistry, 2008
- Enhanced phosphorylation of Nbs1, a member of DNA repair/checkpoint complex Mre11-RAD50-Nbs1, can be targeted to increase the efficacy of imatinib mesylate against BCR/ABL-positive leukemia cellsBlood, 2007
- Epigenetic inactivation of the premature aging Werner syndrome gene in human cancerProceedings of the National Academy of Sciences, 2006
- Rad51 overexpression promotes alternative double-strand break repair pathways and genome instabilityOncogene, 2004