BCR/ABL Stimulates WRN to Promote Survival and Genomic Instability
| Autor: | Dariusz Pytel, Tomasz Poplawski, Michał Nowicki, Tomasz Skorski, Kimberly Cramer, Artur Slupianek, Ewelina Stoczyńska, Stanislaw K. Jozwiakowski, Janusz Blasiak |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
Genome instability
congenital hereditary and neonatal diseases and abnormalities Cancer Research Werner Syndrome Helicase DNA Repair DNA repair Recombinant Fusion Proteins Fusion Proteins bcr-abl Biology Philadelphia chromosome Genomic Instability Article Mice Cell Line Tumor Leukemia Myelogenous Chronic BCR-ABL Positive hemic and lymphatic diseases medicine Animals Humans DNA Breaks Double-Stranded Phosphorylation education Chromosome Aberrations education.field_of_study ABL RecQ Helicases breakpoint cluster region nutritional and metabolic diseases Myeloid leukemia DNA Neoplasm Protein-Tyrosine Kinases medicine.disease Oxidative Stress Exodeoxyribonucleases Oncology Disease Progression Cancer research Homologous recombination |
| Zdroj: | Cancer Research. 71:842-851 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/0008-5472.can-10-1066 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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