title: AT cells are not radiosensitive for simple chromosomal exchanges at low dose.
abstract: Cells deficient in ATM (product of the gene that is mutated in ataxia telangiectasia patients) or NBS (product of the gene mutated in the Nijmegen breakage syndrome) show increased yields of both simple and complex chromosomal aberrations after high doses (>0.5Gy) of ionizing radiation (X-rays or γ-rays), however less is known on how these cells respond at low dose. Previously we had shown that the increased chromosome aberrations in ATM and NBS defective lines was due to a significantly larger quadratic dose-response term compared to normal fibroblasts for both simple and complex exchanges. The linear dose-response term for simple exchanges was significantly higher in NBS cells compared to wild type cells, but not for AT cells. However, AT cells have a high background level of exchanges compared to wild type or NBS cells that confounds the understanding of low dose responses. To understand the sensitivity differences for high to low doses, chromosomal aberration analysis was first performed at low dose-rates (0.5Gy/d), and results provided further evidence for the lack of sensitivity for exchanges in AT cells below doses of 1Gy. Normal lung fibroblast cells treated with KU-55933, a specific ATM kinase inhibitor, showed increased numbers of exchanges at a dose of 1Gy and higher, but were similar to wild type cells at 0.5Gy or below. These results were confirmed using siRNA knockdown of ATM. The present study provides evidence that the increased radiation sensitivity of AT cells for chromosomal exchanges found at high dose does not occur at low dose.
authors: USRA Division of Life Sciences, Houston, TX 77058, USA.
authors: Megumi
authors: M
authors: Hada
authors: Janice L
authors: JL
authors: Huff
authors: Zarana S
authors: ZS
authors: Patel
authors: Tetsuya
authors: T
authors: Kawata
authors: Janice M
authors: JM
authors: Pluth
authors: Kerry A
authors: KA
authors: George
authors: Francis A
authors: FA
authors: Cucinotta
mesh_terms: D001260:Ataxia Telangiectasia / Q000235:genetics*; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000235:genetics; D002460:Cell Line; D002869:Chromosome Aberrations / Q000528:radiation effects*; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000235:genetics; D004307:Dose-Response Relationship, Radiation; D005347:Fibroblasts; D005720:Gamma Rays; D055785:Gene Knockdown Techniques; D006801:Humans; D009025:Morpholines / Q000494:pharmacology; D009687:Nuclear Proteins / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D011753:Pyrones / Q000494:pharmacology; D011836:Radiation Tolerance / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: C495818:2-morpholin-4-yl-6-thianthren-1-yl-pyran-4-one; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D009025:Morpholines; C112156:NBN protein, human; D009687:Nuclear Proteins; D011753:Pyrones; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases