The principle objective of this research proposal is to evaluate the role of molecular damage and cellular lesions in radiation-induced cell death from the decay of the molecular damage producing agent, 125I. The nucleus is generally believed to contain the radiation-sensitive target(s) for cell death. 125I decay in the nucleus causes extensive DNA damage and is very cytotoxic but the mechanism(s) leading to cell death is unknown. In order to gain further insight into mechanism(s) of cell lethality, we propose to investigate the role of the location of lesion(s) produced by 125I decay in chromatin in relation to cellular radiosensitivity. Any modification of radiosensitivity by the extent of DNA damage (DNA single strand breaks, DNA double strand breaks and DNA-protein cross links) and repair (measured by alkaline and neutral filter elution) , repair patch distribution (measured by the buoyant density shift method) or chromatin compaction status (measured in cells with differing chromatin compaction due to their cell cycle position, chromatin decondensation produced by isoleucine deprivation, and DNA damage induction in isolated subcellular particles retaining different levels of chromatin compaction) relative to the ultrastructural location of the lesions in chromatin or proximity to potentially critical targets will be evaluated. The systematic evaluation of 125I decay-induced DNA damage and DNA damage repair in relation to the organization of chromatin and then correlation of this information with the cytotoxic endpoint of 125I decay in the cell nucleus may allow characterization of a critical lethal target(s) whose integrity is crucial for the successful reproductive functioning of the cell.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29CA045011-05
Application #
3458226
Study Section
Radiation Study Section (RAD)
Project Start
1987-05-01
Project End
1992-04-30
Budget Start
1990-05-01
Budget End
1991-04-30
Support Year
5
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Northern Illinois University
Department
Type
Schools of Arts and Sciences
DUNS #
City
De Kalb
State
IL
Country
United States
Zip Code
60115
Yasui, L S; Fink, T J; Enrique, A M (1994) Nuclear scaffold organization in the X-ray sensitive Chinese hamster mutant cell line, xrs-5. Int J Radiat Biol 65:185-92
Korte, C C; Yasui, L S (1993) Morphological characterization of the radiation sensitive cell line, xrs-5. Scanning Microsc 7:943-51
Yasui, L S (1992) Cytotoxicity of 125I decay in the DNA double strand break repair deficient mutant cell line, xrs-5. Int J Radiat Biol 62:613-8
Schwartz, J L; Moan, E; Mustafi, R et al. (1992) Faster rates of DNA unwinding under alkaline conditions in xrs-5 cells may reflect chromatin structure alterations. Mutat Res 282:13-7
Yasui, L S; Ling-Indeck, L; Johnson-Wint, B et al. (1991) Changes in the nuclear structure in the radiation-sensitive CHO mutant cell, xrs-5. Radiat Res 127:269-77
Yasui, L S; Fink, T J (1990) Thermal sensitivity of CHO cells with different shapes. Int J Hyperthermia 6:57-65
Flick, M B; Warters, R L; Yasui, L S et al. (1989) Measurement of radiation-induced DNA damage using gel electrophoresis or neutral filter elution shows an increased frequency of DNA strand breaks after exposure to pH 9.6. Radiat Res 119:452-65
Yasui, L S; Higashikubo, R; Warters, R L (1987) The effect of chromatin decondensation on DNA damage and repair. Radiat Res 112:318-30