Deficiency of Bloom syndrome helicase activity is radiomimetic.
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.
Horowitz
David P
DP
Department of Radiation Oncology and Molecular Radiation Sciences, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Topaloglu
Ozlem
O
Zhang
Yonggang
Y
Bunz
Fred
F
D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D001816:Bloom Syndrome / Q000235:genetics / Q000532:radiotherapy; D018797:Cell Cycle Proteins / Q000378:metabolism; D064447:Checkpoint Kinase 2; D004268:DNA-Binding Proteins / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D006720:Homozygote; D006801:Humans; D051379:Mice; D009154:Mutation; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011836:Radiation Tolerance; D011839:Radiation, Ionizing; D053484:RecQ Helicases / Q000172:deficiency* / Q000235:genetics*; D012854:Sister Chromatid Exchange; D025521:Tumor Suppressor Proteins / Q000378:metabolism
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; D064447:Checkpoint Kinase 2; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; C578634:CHEK2 protein, human; C578633:Chek2 protein, mouse; D017346:Protein Serine-Threonine Kinases; C097151:Bloom syndrome protein; D053484:RecQ Helicases
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