BCR/ABL oncogenic kinase promotes unfaithful repair of the reactive oxygen species-dependent DNA double-strand breaks.
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 G(2)/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.
Center for Biotechnology, College of Science and Technology, Temple University, Bio-Life Sciences Bldg, Rm 419, 1900 N 12th St, Philadelphia, PA 19122, USA.
Michal O
MO
Nowicki
Rafal
R
Falinski
Mateusz
M
Koptyra
Artur
A
Slupianek
Tomasz
T
Stoklosa
Ewa
E
Gloc
Margaret
M
Nieborowska-Skorska
Janusz
J
Blasiak
Tomasz
T
Skorski
D000818:Animals; D020552:Comet Assay; D004249:DNA Damage; D004260:DNA Repair; D016044:Fusion Proteins, bcr-abl / Q000502:physiology*; D042822:Genomic Instability; D007399:Interphase; D007938:Leukemia / Q000209:etiology; D051379:Mice; D009154:Mutation; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D017382:Reactive Oxygen Species; D016044:Fusion Proteins, bcr-abl