Steven M. Yannone1, Sandeep Burma1, Elina
Golder-Novoselsky1, Hatsumi Nagasawa2, John Little2
and David J Chen1
1Life Sciences Division, Department of Cell and Molecular
Biology, Lawrence Berkeley National Laboratory, Mail stop 74-157, 1 Cyclotron
Road, Berkeley, California 94720 and 2Harvard School of Public
Health, Department of Cancer Cell Biology, Boston, Massachusetts 02115
A central challenge in risk assessment for low-level ionizing radiation (LLIR) exposure is defining and quantifying biological responses to low levels of ionizing radiation. To address this problem and provide a possible means to assess the risks associated with LLIR exposure in humans, we have taken a multifaceted approach. Our approaches include: 1) the genome-wide identification of genes whose transcription is regulated in response to LLIR. This will provide us with a molecular readout for the cellular transcriptional response to LLIR exposure as well as providing specific expression patterns, which may be used to evaluate LLIR exposure risks. We have observed differences in global gene expression patterns between low and high doses of radiation, and are currently identifying the genes that respond specifically to low or high dose. 2) We are also using transgenic mouse cells deficient in specific DNA repair proteins to evaluate the effect of specific genetic deficiencies on the cellular response to LLIR and to identify the genes/pathways that mediate the response to LLIR. We are also using the more traditional biological endpoints, sister chromatid exchange, chromosomal aberrations, and HPRT mutations to evaluate the cellular response to LLIR and to corroborate the cDNA microarray data. These approaches will help us to understand the mechanism(s) of cellular response to LLIR. 3) Finally, we would like to identify the cellular and molecular targets that mediate bystander effects in response to LLIR. We hypothesize that the biological end points of bystander effects are mediated by reactive oxygen species (ROS) and plan to identify DNA-damage signaling pathways and genes that may potentially mediate these effects. We shall again use transgenic mouse models to identify specific DNA repair genes and pathways that may be involved in induction of bystander effects. We have observed increased effects of LLIR induced bystander effects in DNA-PK deficient cells, indicating that double-strand break repair pathways play an important role in the bystander effect. Comparisons of global and specific gene expression patterns between LLIR and the bystander effect will help identify potential LLIR or ROS-induced transcripts that may mediate these responses.