BCR/ABL oncogenic kinase promotes unfaithful repair of the reactive oxygen species–dependent DNA double-strand breaks
- 1 December 2004
- journal article
- Published by American Society of Hematology in Blood
- Vol. 104 (12), 3746-3753
- https://doi.org/10.1182/blood-2004-05-1941
Abstract
The oncogenic BCR/ABL tyrosine kinase induces constitutive DNA damage in Philadelphia chromosome (Ph)-positive leukemia cells. We find that BCR/ABL-induced reactive oxygen species (ROSs) cause chronic oxidative DNA damage resulting in double-strand breaks (DSBs) in S and G2/M cell cycle phases. These lesions are repaired by BCR/ABL-stimulated homologous recombination repair (HRR) and nonhomologous end-joining (NHEJ) mechanisms. A high mutation rate is detected in HRR products in BCR/ABL-positive cells, but not in the normal counterparts. In addition, large deletions are found in NHEJ products exclusively in BCR/ABL cells. We propose that the following series of events may contribute to genomic instability of Ph-positive leukemias: BCR/ABL → ROSs → oxidative DNA damage → DSBs in proliferating cells → unfaithful HRR and NHEJ repair.Keywords
This publication has 69 references indexed in Scilit:
- The biology of CML blast crisisBlood, 2004
- Mechanism and regulation of human non-homologous DNA end-joiningNature Reviews Molecular Cell Biology, 2003
- Pathways of DNA Double-Strand Break Repair during the Mammalian Cell CycleMolecular and Cellular Biology, 2003
- Down-regulation of BRCA1 in BCR-ABL–expressing hematopoietic cellsBlood, 2003
- Oxidative nucleotide damage: consequences and preventionOncogene, 2002
- Involvement of DNA polymerase β in DNA replication and mutagenic consequencesJournal of Molecular Biology, 2002
- Mutator phenotype of BCR – ABL transfected Ba/F3 cell lines and its association with enhanced expression of DNA polymerase βOncogene, 1999
- Origin of Multiple Mutations in Human CancersDrug Metabolism Reviews, 1998
- A simple technique for quantitation of low levels of DNA damage in individual cellsExperimental Cell Research, 1988
- A table for the estimation of the spontaneous mutations rate of cells in cultureMutation Research - Reviews in Mutation Research, 1973