Studies are proposed to gain insight into molecular genetic mechanisms underlying the processing of radiation damage and the consequences of that processing. Preliminary studies with a pair of isogeneic human fibrosarcoma cell lines differing only in their p53 status have resulted in the following observations: 1) The G1 and G2 checkpoints appear to have a certain redundancy, 2) The G2 checkpoint appears to have both p53-dependent and - independent components, and 3) The proto-oncogene stathmin appears to alter p53-mediated cell cycle arrest. Experiments are proposed using synchronized cell populations to investigate the role of G1 and G2 checkpoints in chromosome aberration induction, clonogenic survival, mutation induction, and the kinetics of cell cycle progression, all following ionizing irradiation. These experiments should provide information on the impact of cell cycle checkpoints on radiation-induced cellular lethality and genetic instability. Investigations into the mechanism underlying the prolonged G1 arrest in normal human diploid skin fibroblasts have the potential to further elucidate the role of various steps in the integrin signal transduction pathway in influencing radiation-induced cell cycle arrest and genetic stability.
| Wang, Xiao Qi; Stanbridge, Eric J; Lao, Xiaoyan et al. (2007) p53-dependent Chk1 phosphorylation is required for maintenance of prolonged G2 Arrest. Radiat Res 168:706-15 |
| Wang, Xiao Qi; Redpath, J Leslie; Fan, Sheung Tat et al. (2006) ATR dependent activation of Chk2. J Cell Physiol 208:613-9 |
| DeSimone, John N; Bengtsson, Ulla; Wang, XiaoQi et al. (2003) Complexity of the mechanisms of initiation and maintenance of DNA damage-induced G2-phase arrest and subsequent G1-phase arrest: TP53-dependent and TP53-independent roles. Radiat Res 159:72-85 |
| Leslie Redpath, J; Bengtsson, Ulla; DeSimone, John et al. (2003) Sticky anaphase aberrations after G2-phase arrest of gamma-irradiated human skin fibroblasts: TP53 independence of formation and TP53 dependence of consequences. Radiat Res 159:57-71 |
| DeSimone, J N; Dolezalova, H; Redpath, J L et al. (2000) Prolonged cell cycle arrest in irradiated human diploid skin fibroblasts: the role of nutrient deprivation. Radiat Res 153:131-43 |
