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

Cancer Cell. 2004 Mar;5(3):275-85. doi: 10.1016/s1535-6108(04)00056-x.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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

Substances

  • Cell Cycle Proteins
  • Enzyme Inhibitors
  • Etoposide
  • Fusion Proteins, bcr-abl
  • ATR protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Protein-Serine-Threonine Kinases
  • DNA Topoisomerases, Type II