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DNA Repair Defects and Chromosomal AberrationsYields of chromosome aberrations were assessed in cells deficient in DNA doublestrand break (DSB) repair, after exposure to acute or to low-dose-rate (0.018 Gy/hr) gamma rays or acute high LET iron nuclei. We studied several cell lines including fibroblasts deficient in ATM (ataxia telangiectasia 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. Chromosomes were analyzed using the fluorescence in situ hybridization (FISH) chromosome painting method in cells at the first division post irradiation, and chromosome aberrations were identified as either simple exchanges (translocations and dicentrics) or complex exchanges (involving >2 breaks in 2 or more chromosomes). Gamma irradiation induced greater yields of both simple and complex exchanges in the DSB repair-defective cells than in the normal cells. The quadratic dose-response terms for both simple and complex chromosome exchanges were significantly higher for the ATM- and NBS-deficient lines than for normal fibroblasts. However, in the NBS cells the linear dose-response term was significantly higher only for simple exchanges. The large increases in the quadratic dose-response terms in these repair-defective cell lines points the importance of the functions of ATM and NBS in chromatin modifications to facilitate correct DSB repair and minimize the formation of aberrations. The differences found between ATM- and NBS-deficient cells at low doses suggest that important questions should with regard to applying observations of radiation sensitivity at high dose to low-dose exposures. For aberrations induced by iron nuclei, regression models preferred purely linear dose responses for simple exchanges and quadratic dose responses for complex exchanges. Relative biological effectiveness (RBE) factors of all of the DNA repair-defective cell lines were smaller than those of normal cells, with the DNA-PK-deficient cells having RBEs near unity. To further investigate the sensitivity differences that were observed in ATM and NBS deficient cells, chromosomal aberrations were analyzed in normal lung fibroblast cells treated with KU-55933 (a specific ATM kinase inhibitor) or Mirin (an Mre11- Rad50-Nbs1 complex inhibitor involved in activation of ATM). We also performed siRNA knockdown of these proteins. Preliminary data indicate that chromosome exchanges increase in 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
Document Type
Conference Paper
Hada, Megumi
(Universities Space Research Association Houston, TX, United States)
George, K. A.
(Wyle Labs., Inc. Houston, TX, United States)
Huff, J. L.
(Universities Space Research Association Houston, TX, United States)
Pluth, J. M.
(California Univ., Lawrence Berkeley National Lab. Berkeley, CA, 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
Life Sciences (General)
Report/Patent Number
Meeting Information
Meeting: Heavy Ions in Therapy and Space Symposium
Location: Cologne
Country: Germany
Start Date: July 6, 2009
End Date: July 10, 2009
Sponsors: Gesellschaft fuer Schwerionenforschung m.b.H., NASA Headquarters, European Space Agency, Deutsches Zentrum fuer Luft- und Raumfahrt e.V.
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