BCR/ABL translocates to the nucleus and disrupts an ATR-dependent intra-S phase checkpoint.
Chronic myelogeneous leukemia (CML) is a two-stage disease associated with expression of the BCR/ABL tyrosine kinase protein. However, whether BCR/ABL expression directly causes blast crisis, and if so by what mechanism, is unknown. We have found that BCR/ABL translocates from the cytoplasm to the nucleus after genotoxic stress. Furthermore, BCR/ABL increases DNA double-strand damage after etoposide treatment and leads to a defect in an intra-S phase checkpoint, causing a radioresistant DNA synthesis (RDS) phenotype. In the nucleus, BCR/ABL associates with the ataxia-telangiectasia and rad 3-related protein (ATR) and disrupts ATR-dependent signal transduction. Overexpression of ATR in a BCR/ABL-expressing cell line corrects the DNA damage phenotype. These results demonstrate a nuclear role for BCR/ABL in altering the cellular response to DNA damage.
Dierov
Jamil
J
Division of Hematology and Oncology, University of Pennsylvania, Philadelphia, PA 19104, USA.
Dierova
Raia
R
Carroll
Martin
M
D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D003593:Cytoplasm / Q000378:metabolism; D004249:DNA Damage / Q000502:physiology; D004260:DNA Repair / Q000502:physiology; D004250:DNA Topoisomerases, Type II / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000503:physiopathology; D017346:Protein Serine-Threonine Kinases; D021381:Protein Transport / Q000502:physiology; D016196:S Phase / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology
D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D005047:Etoposide; D016044:Fusion Proteins, bcr-abl; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D004250:DNA Topoisomerases, Type II