BCR/ABL stimulates WRN to promote survival and genomic instability.
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.
Department of Microbiology and Immunology, School of Medicine, Temple University, Philadelphia, Pennsylvania 19140, USA.
Artur
A
Slupianek
Tomasz
T
Poplawski
Stanislaw K
SK
Jozwiakowski
Kimberly
K
Cramer
Dariusz
D
Pytel
Ewelina
E
Stoczynska
Michal O
MO
Nowicki
Janusz
J
Blasiak
Tomasz
T
Skorski
D000818:Animals; D045744:Cell Line, Tumor; D002869:Chromosome Aberrations; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D004273:DNA, Neoplasm / Q000235:genetics; D018450:Disease Progression; D005090:Exodeoxyribonucleases / Q000235:genetics* / Q000378:metabolism; D016044:Fusion Proteins, bcr-abl / Q000235:genetics* / Q000378:metabolism; D042822:Genomic Instability; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018384:Oxidative Stress / Q000235:genetics; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D053484:RecQ Helicases / Q000235:genetics* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D000071657:Werner Syndrome Helicase
D004273:DNA, Neoplasm; D011993:Recombinant Fusion Proteins; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; D005090:Exodeoxyribonucleases; D053484:RecQ Helicases; C098785:WRN protein, human; D000071657:Werner Syndrome Helicase; C499253:Wrn protein, mouse