BCR/ABL translocates to the nucleus and disrupts an ATR-dependent intra-S phase checkpoint

• Published in: Cancer cell Vol. 5; no. 3; pp. 275 - 285
• Main Authors: Dierov, Jamil, Dierova, Raia, Carroll, Martin
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-03-2004
• Subjects: Ataxia Telangiectasia Mutated Proteins; Cell Cycle Proteins - metabolism; Cell Nucleus - metabolism; Cells, Cultured; Cytoplasm - metabolism; DNA Damage - physiology; DNA Repair - physiology; DNA Topoisomerases, Type II - drug effects; Enzyme Inhibitors - pharmacology; Etoposide - pharmacology; Fusion Proteins, bcr-abl - metabolism; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - physiopathology; Protein Transport - physiology; Protein-Serine-Threonine Kinases; S Phase - physiology; Signal Transduction - physiology
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/S1535-6108(04)00056-X

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.