BCR/ABL regulates mammalian RecA homologs, resulting in drug resistance.
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.
Slupianek
A
A
Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA.
Schmutte
C
C
Tombline
G
G
Nieborowska-Skorska
M
M
Hoser
G
G
Nowicki
M O
MO
Pierce
A J
AJ
Fishel
R
R
Skorski
T
T
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D002945:Cisplatin / Q000494:pharmacology; D004260:DNA Repair / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004351:Drug Resistance / Q000502:physiology*; D004789:Enzyme Activation; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism*; D017930:Genes, Reporter / Q000235:genetics; D006801:Humans; D007377:Interleukin-3 / Q000494:pharmacology; D008856:Microscopy, Fluorescence; D008894:Milk Proteins; D016685:Mitomycin / Q000494:pharmacology; D010766:Phosphorylation; D051135:Rad51 Recombinase; D011938:Rec A Recombinases / Q000235:genetics / Q000378:metabolism*; D050799:STAT5 Transcription Factor; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation
D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D061945:Caspase Inhibitors; D004268:DNA-Binding Proteins; D007377:Interleukin-3; D008894:Milk Proteins; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D016685:Mitomycin; D016044:Fusion Proteins, bcr-abl; C495153:RAD51 protein, human; D051135:Rad51 Recombinase; D011938:Rec A Recombinases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D002945:Cisplatin