Year

2011

Type(s)

Journal Article

Author(s)

Slupianek, Artur and Poplawski, Tomasz and Jozwiakowski, Stanislaw K. and Cramer, Kimberly and Pytel, Dariusz and Stoczynska, Ewelina and Nowicki, Michal O. and Blasiak, Janusz and Skorski, Tomasz

Source

Cancer Research, 71(3): 842—851, 2011

BibTeX

BibTeX

BibTeX

@article{slupianek_bcr/abl_2011, title = {{BCR}/{ABL} stimulates {WRN} to promote survival and genomic instability}, volume = {71}, issn = {1538-7445}, doi = {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.}, language = {eng}, number = {3}, journal = {Cancer Research}, author = {Slupianek, Artur and Poplawski, Tomasz and Jozwiakowski, Stanislaw K. and Cramer, Kimberly and Pytel, Dariusz and Stoczynska, Ewelina and Nowicki, Michal O. and Blasiak, Janusz and Skorski, Tomasz}, month = feb, year = {2011}, pmid = {21123451}, pmcid = {PMC3032814}, keywords = {Humans, Animals, DNA Repair, Cell Line, Tumor, Genomic Instability, Disease Progression, DNA, Neoplasm, Fusion Proteins, bcr-abl, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Protein-Tyrosine Kinases, Oxidative Stress, DNA Breaks, Double-Stranded, Chromosome Aberrations, Exodeoxyribonucleases, Mice, Phosphorylation, Recombinant Fusion Proteins, RecQ Helicases}, pages = {842--851}