title: Deficiency of Bloom syndrome helicase activity is radiomimetic.
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.
authors.affiliation: Department of Radiation Oncology and Molecular Radiation Sciences, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: David P
authors.initials: DP
authors.lastname: Horowitz
authors.forename: Ozlem
authors.initials: O
authors.lastname: Topaloglu
authors.forename: Yonggang
authors.initials: Y
authors.lastname: Zhang
authors.forename: Fred
authors.initials: F
authors.lastname: Bunz
mesh_terms: 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
chemical_list: 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
references.citation: Cancer Res. 2003 Dec 15;63(24):8578-81
references.pmid: 14695165
references.citation: Nucleic Acids Res. 2000 Jun 15;28(12):2420-30
references.pmid: 10871376
references.citation: Carcinogenesis. 1986 Jan;7(1):53-7
references.pmid: 3943145
references.citation: Nat Cell Biol. 2006 Jan;8(1):37-45
references.pmid: 16327781
references.citation: Proc Natl Acad Sci U S A. 2000 May 9;97(10):5214-9
references.pmid: 10779560
references.citation: Genes Dev. 1998 Nov 1;12(21):3382-93
references.pmid: 9808625
references.citation: Nature. 2003 Dec 18;426(6968):870-4
references.pmid: 14685245
references.citation: Mol Cell Biol. 2004 Feb;24(3):1279-91
references.pmid: 14729972
references.citation: Nat Genet. 2000 Dec;26(4):424-9
references.pmid: 11101838
references.citation: Mol Cell Biol. 2005 Aug;25(16):7158-69
references.pmid: 16055725
references.citation: Genes Dev. 2001 Sep 1;15(17):2177-96
references.pmid: 11544175
references.citation: Trends Cell Biol. 2002 Nov;12(11):509-16
references.pmid: 12446112
references.citation: Science. 2007 May 25;316(5828):1160-6
references.pmid: 17525332
references.citation: Cell. 2002 Dec 13;111(6):779-89
references.pmid: 12526805
references.citation: J Biol Chem. 2000 Aug 4;275(31):23500-8
references.pmid: 10825162
references.citation: Oncogene. 2003 Nov 27;22(54):8749-57
references.pmid: 14647470
references.citation: Proc Natl Acad Sci U S A. 1975 Feb;72(2):758-62
references.pmid: 1054854
references.citation: Nat Rev Cancer. 2003 Mar;3(3):169-78
references.pmid: 12612652
references.citation: Nature. 2003 Jan 30;421(6922):499-506
references.pmid: 12556884
references.citation: Cancer Res. 2006 Feb 15;66(4):2233-41
references.pmid: 16489026
references.citation: Science. 1998 Dec 4;282(5395):1893-7
references.pmid: 9836640
references.citation: Nat Med. 1997 Sep;3(9):962-3
references.pmid: 9288720
references.citation: Oncogene. 2007 Apr 19;26(18):2535-42
references.pmid: 17043640
references.citation: Mol Cell Biol. 2001 Jul;21(13):4129-39
references.pmid: 11390642
references.citation: Mol Cancer Res. 2007 Jul;5(7):713-24
references.pmid: 17634426
references.citation: J Clin Invest. 1999 Aug;104(3):263-9
references.pmid: 10430607