Abstract
Bloom syndrome is caused by homozygous mutations in BLM, which encodes a RecQ DNA helicase. Patient-derived cells deficient in BLM helicase activity exhibit genetic instability--apparent cytogenetically as sister chromatid exchanges--and activated DNA damage signaling. In this report, we show that BLM-knockout colorectal cancer cells exhibited endogenous, ATM-dependent double-strand DNA break responses similar to those recently observed in Bloom syndrome patient-derived cells. Xenograft tumors established from BLM-deficient cancer cells were not radiosensitive, but exhibited growth impairment that was comparable to that of wild type tumors treated with a single, high dose of ionizing radiation. These results suggest that pharmacological inhibitors of BLM would have a radiomimetic effect and that transient inhibition of BLM activity might be a viable strategy for anticancer therapy.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Ataxia Telangiectasia Mutated Proteins
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Bloom Syndrome / genetics
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Bloom Syndrome / radiotherapy
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Cell Cycle Proteins / metabolism
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Checkpoint Kinase 2
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DNA-Binding Proteins / metabolism
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Genetic Predisposition to Disease
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Homozygote
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Humans
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Mice
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Mutation*
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Neoplasm Transplantation
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Phosphorylation
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Protein Serine-Threonine Kinases / metabolism
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Radiation Tolerance*
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Radiation, Ionizing
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RecQ Helicases / deficiency*
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RecQ Helicases / genetics*
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Sister Chromatid Exchange
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Tumor Suppressor Proteins / metabolism
Substances
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Cell Cycle Proteins
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DNA-Binding Proteins
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Tumor Suppressor Proteins
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Checkpoint Kinase 2
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ATM protein, human
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Ataxia Telangiectasia Mutated Proteins
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Atm protein, mouse
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CHEK2 protein, human
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Chek2 protein, mouse
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Protein Serine-Threonine Kinases
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Bloom syndrome protein
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RecQ Helicases