Abstract
RAD51 is one of six mitotic human homologs of the E. coli RecA protein (RAD51-Paralogs) that play a central role in homologous recombination and repair of DNA double-strand breaks (DSBs). Here we demonstrate that RAD51 is important for resistance to cisplatin and mitomycin C in cells expressing the BCR/ABL oncogenic tyrosine kinase. BCR/ABL significantly enhances the expression of RAD51 and several RAD51-Paralogs. RAD51 overexpression is mediated by a STAT5-dependent transcription as well as by inhibition of caspase-3-dependent cleavage. Phosphorylation of the RAD51 Tyr-315 residue by BCR/ABL appears essential for enhanced DSB repair and drug resistance. Induction of the mammalian RecA homologs establishes a unique mechanism for DNA damage resistance in mammalian cells transformed by an oncogenic tyrosine kinase.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Antibiotics, Antineoplastic / pharmacology
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Antineoplastic Agents / pharmacology
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Apoptosis / drug effects
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Apoptosis / physiology
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Bone Marrow Cells / drug effects
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Bone Marrow Cells / metabolism
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Caspase 3
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Caspase Inhibitors
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Caspases / metabolism
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Cell Line
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Cisplatin / pharmacology
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DNA Repair / physiology*
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Drug Resistance / physiology*
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Enzyme Activation
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Fusion Proteins, bcr-abl / genetics
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Fusion Proteins, bcr-abl / metabolism*
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Genes, Reporter / genetics
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Humans
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Interleukin-3 / pharmacology
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Microscopy, Fluorescence
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Milk Proteins*
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Mitomycin / pharmacology
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Phosphorylation
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Rad51 Recombinase
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Rec A Recombinases / genetics
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Rec A Recombinases / metabolism*
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STAT5 Transcription Factor
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Trans-Activators / genetics
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Trans-Activators / metabolism
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Transcriptional Activation
Substances
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Antibiotics, Antineoplastic
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Antineoplastic Agents
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Caspase Inhibitors
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DNA-Binding Proteins
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Interleukin-3
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Milk Proteins
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STAT5 Transcription Factor
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Trans-Activators
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Mitomycin
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Fusion Proteins, bcr-abl
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RAD51 protein, human
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Rad51 Recombinase
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Rec A Recombinases
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CASP3 protein, human
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Caspase 3
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Caspases
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Cisplatin