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Analysis of Chromosomal Aberrations after Low and High Dose Rate Gamma Irradiation in ATM or NBS Suppressed Human Fibroblast CellsA detailed understanding of the biological effects of heavy nuclei is needed for space radiation protection and for cancer therapy. High-LET radiation produces more complex DNA lesions that may be non-repairable or that may require additional processing steps compared to endogenous DSBs, increasing the possibility of misrepair. Interplay between radiation sensitivity, dose, and radiation quality has not been studied extensively. Previously we studied chromosome aberrations induced by low- and high- LET radiation in several cell lines deficient in ATM (ataxia telangactasia mutated; product of the gene that is mutated in ataxia telangiectasia patients) or NBS (nibrin; product of the gene mutated in the Nijmegen breakage syndrome), and gliomablastoma cells that are proficient or lacking in DNA-dependent protein kinase (DNA-PK) activity. We found that the yields of both simple and complex chromosomal aberrations were significantly increased in the DSB repair defective cells compared to normal cells. The increased aberrations observed for the ATM and NBS defective lines was due to a significantly larger quadratic dose-response term compared to normal fibroblasts for both simple and complex aberrations, while the linear dose-response term was significantly higher in NBS cells only for simple exchanges. These results point to the importance of the functions of ATM and NBS in chromatin modifications that function to facilitate correct DSB repair and minimize aberration formation. To further understand the sensitivity differences that were observed in ATM and NBS deficient cells, in this study, chromosomal aberration analysis was performed in normal lung fibroblast cells treated with KU-55933, a specific ATM kinase inhibitor, or Mirin, an MRN complex inhibitor involved in activation of ATM. We are also testing siRNA knockdown of these proteins. Normal and ATM or NBS suppressed cells were irradiated with gamma-rays and chromosomes were collected with a premature chromosome condensation (PCC) technique at the first mitosis post-irradiation. Chromosomes were analyzed using a multicolor fluorescence in-situ hybridization (mFISH) chromosome painting method. Preliminary analysis showed that chromosomal exchanges were increased in the cells treated with the specific ATM inhibitor. Possible cytogenetic signatures of acute and low dose-rate gamma irradiation in ATM or Nibrin deficient and suppressed cells will be discussed.
Document ID
20090015363
Acquisition Source
Johnson Space Center
Document Type
Conference Paper
Authors
Hada, M.
(Universities Space Research Association Houston, TX, United States)
Huff, J. L.
(Universities Space Research Association Houston, TX, United States)
Patel, Z.
(Universities Space Research Association Houston, TX, United States)
Pluth, J. M.
(California Univ., Lawrence Berkeley National Lab. Berkeley, CA, United States)
George, K. A.
(Wyle Labs., Inc. Houston, TX, United States)
Cucinotta, F. A.
(NASA Johnson Space Center Houston, TX, United States)
Date Acquired
August 24, 2013
Publication Date
January 1, 2009
Subject Category
Space Radiation
Report/Patent Number
JSC-18122
Meeting Information
Meeting: 55th Annual Meeting of the Radiation Research
Location: Savannah, GA
Country: United States
Start Date: October 4, 2009
End Date: October 7, 2009
Distribution Limits
Public
Copyright
Other

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