BLM helicase is activated in BCR/ABL leukemia cells to modulate responses to cisplatin.
Bloom protein (BLM) is a 3'-5' helicase, mutated in Bloom syndrome, which plays an important role in response to DNA double-strand breaks and stalled replication forks. Here, we show that BCR/ABL tyrosine kinase, which also modulates DNA repair capacity, is associated with elevated expression of BLM. Downregulation of BLM by antisense cDNA or dominant-negative mutant inhibits homologous recombination repair (HRR) and increases sensitivity to cisplatin in BCR/ABL-positive cells. Bone marrow cells from mice heterozygous for BLM mutation, BLM(Cin/+), transfected with BCR/ABL display increased sensitivity to cisplatin compared to those obtained from the wild-type littermates. BCR/ABL promotes interactions of BLM with RAD51, while simultaneous overexpression of BLM and RAD51 in normal cells increases drug resistance. These data suggest that BLM collaborates with RAD51 to facilitate HRR and promotes the resistance of BCR/ABL-positive leukemia cells to DNA-damaging agents.
Slupianek
Artur
A
Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA.
Gurdek
Ewa
E
Koptyra
Mateusz
M
Nowicki
Michal O
MO
Siddiqui
Khwaja M
KM
Groden
Joanna
J
Skorski
Tomasz
T
D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000633:toxicity; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism*; D004260:DNA Repair; D016373:DNA, Antisense; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007938:Leukemia; D051379:Mice; D009154:Mutation; D051135:Rad51 Recombinase; D053484:RecQ Helicases; D011995:Recombination, Genetic; D014162:Transfection
D016373:DNA, Antisense; D004268:DNA-Binding Proteins; D016044:Fusion Proteins, bcr-abl; C495153:RAD51 protein, human; D051135:Rad51 Recombinase; C495154:Rad51 protein, mouse; D000251:Adenosine Triphosphatases; C097151:Bloom syndrome protein; D004265:DNA Helicases; D053484:RecQ Helicases; D002945:Cisplatin