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(PP265) Genome-wide changes in gene expression in primary human fibroblasts in response to I-125-induced DNA damage.
Sokolov, Mykyta*,1, Smirnova, Nataliya2, Camerini-Otero, Daniel2, Panyutin, Igor1, Neumann, Ronald1, 1 Department of Nuclear Medicine, Bethesda, MD, US2 Genetics and Biochemistry Branch and Laboratory of Cellular and Developmental Biology, Bethesda, MD, US
ABSTRACT- Although several reports dealing with the identification of radiation-inducible genes on a large-scale basis have been published thus far, transcriptional responses to DNA damage have not been yet fully characterized in human cells. To identify a whole human genome-wide signature of the cellular response to radiation-induced DNA damage, we used Agilent oligo DNA microarrays to study the expression changes of more than 44,000 transcriptional targets in the normal IMR-90 human lung fibroblast cell line. DNA damage was elicited by cell culture exposure either to external low-LET gamma-radiation from Co-60 or to internal high-LET-like from decay of I-125-labeled deoxyuridine (I-125UdR). We found that the set of gamma-radiation-responsive genes that show consistent differential expression after acute (1 Gy, 1 min) as well as chronic (1 Gy, 22 hrs) gamma-radiation exposure comprises about 5% of the total number of all known and predicted genes in the human genome. The profiles of either up- or down-regulated genes following acute and chronic gamma-radiation share between 64%-74% genes in common, with many genes detected as radiation-responsive for the first time. Only 0.5% of the total number of genes in the human genome are differentially expressed in I-125UdR-labeled cells. With a few exceptions, the expression level of all I-125UdR-responsive genes is also found to be significantly altered in cells following gamma-radiation. Oxidative phosphorylation, metabolism of nucleotides and cell cycle regulation are among the up-regulated biological processes mostly affected by gamma-radiation in IMR-90 cells. Certain general metabolism processes such as glycolysis, as well as immune response and translational elongation are downregulated following all of the irradiation protocols used. The results suggest that radiation damage almost exclusively confined to DNA molecules is not the major factor modulating gene expression changes following irradiation. We found no evidence that the high-LET-like DNA damage elicits the expression of a set of genes different from that following low-LET irradiation. Our study identifies novel radiation-responsive genes, improves the current understanding of the cellular response to genotoxic stress and reveals new directions for elucidating the human response to DNA damage.
Key words: DNA microarray, fibroblasts, DNA damage
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