Pharmacological inhibition of c-Abl compromises genetic stability and DNA repair in Bcr-Abl-negative cells

Fanta, S., Sonnenberg, M., Skorta, I., Duyster, J., Miething, C., Aulitzky, W. E., van der Kuip, H. (July 2008) Pharmacological inhibition of c-Abl compromises genetic stability and DNA repair in Bcr-Abl-negative cells. Oncogene, 27 (31). pp. 4380-4384. ISSN 0950-9232

URL: https://www.ncbi.nlm.nih.gov/pubmed/18362889
DOI: 10.1038/onc.2008.68

Abstract

Imatinib inhibits the kinase activity of Bcr-Abl and is currently the most effective drug for treatment of chronic myeloid leukemia (CML). Imatinib also blocks c-Abl, a physiological tyrosine kinase activated by a variety of stress signals including damaged DNA. We investigated the effect of pharmacological inhibition of c-Abl on the processing of irradiation-induced DNA damage in Bcr-Abl-negative cells. Cell lines and peripheral blood mononuclear cells (PBMCs) from healthy volunteers were treated with imatinib or dasatinib before gamma-irradiation. Inhibition of c-Abl caused an enhanced irradiation-induced mutation frequency and slowdown of DNA repair, whereas imatinib was ineffective in cells expressing a T315I variant of c-Abl. Mutation frequency and repair kinetics were also studied in c-Abl-/- murine embryonic fibroblasts (MEFs) retransfected with wild-type c-Abl (wt-Abl) or a kinase-defect variant of Abl (KD-Abl). Enhanced mutation frequency as well as delayed DNA repair was observed in cells expressing KD-Abl. These data indicate that pharmacological inhibition of c-Abl compromises DNA-damage response.

Item Type: Paper
Uncontrolled Keywords: imatinib mesylate c-Abl DNA repair genetic stability CHRONIC MYELOID-LEUKEMIA TYROSINE KINASE INHIBITOR IMATINIB MESYLATE MUTATOR PHENOTYPE DAMAGE PHOSPHORYLATION ASSOCIATION ACTIVATION GROWTH STI571
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification
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organism description > animal > mammal > primates > hominids > human
Investigative techniques and equipment > radiation treatment and equipment > irradiation
diseases & disorders > cancer > cancer types > leukemia
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > mutations
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > kinase > tyrosine kinase
CSHL Authors:
Communities: CSHL labs > Lowe lab
Depositing User: Tom Adams
Date: July 2008
Date Deposited: 13 Jul 2011 14:39
Last Modified: 13 Mar 2018 20:59
Related URLs:
URI: http://repository.cshl.edu/id/eprint/7730

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