BCR/ABL oncogenic kinase promotes unfaithful repair of the reactive oxygen species-dependent DNA double-strand breaks.

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 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.

journal_name

Blood

journal_title

Blood

authors

Nowicki MO,Falinski R,Koptyra M,Slupianek A,Stoklosa T,Gloc E,Nieborowska-Skorska M,Blasiak J,Skorski T

doi

10.1182/blood-2004-05-1941

subject

Has Abstract

pub_date

2004-12-01 00:00:00

pages

3746-53

issue

12

eissn

0006-4971

issn

1528-0020

pii

2004-05-1941

journal_volume

104

pub_type

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