ATM Requirement in Gene Expression Responses to Ionizing Radiation in Human Lymphoblasts and Fibroblasts

Abstract

The heritable disorder ataxia telangiectasia (AT) is caused by mutations in the AT-mutated (ATM) gene with manifestations that include predisposition to lymphoproliferative cancers and hypersensitivity to ionizing radiation (IR). We investigated gene expression changes in response to IR in human lymphoblasts and fibroblasts from seven normal and seven AT-affected individuals. Both cell types displayed ATM-dependent gene expression changes after IR, with some responses shared and some responses varying with cell type and dose. Interestingly, after 5 Gy IR, lymphoblasts displayed ATM-independent responses not seen in the fibroblasts at this dose, which likely reflect signaling through ATM-related kinases, e.g., ATR, in the absence

Ataxia Telangiectasia-Mutated–Dependent DNA Damage Checkpoint Functions Regulate Gene Expression in Human Fibroblasts

“…Further analysis of the expression of these genes in irradiated AT cell lines revealed that p53 target genes were induced by IR in AT2 and AT3 in a delayed pattern as has previously been reported (22,30), but these genes displayed little change in AT1 (Fig. 4A).…”

“…It should be noted that the dose of IR-induced DNA damage can markedly affect the identification of ATMdependent gene expression. For example, whereas AT and normal lymphoblasts showed clear differences in expression of the above-mentioned genes after 1-Gy IR, after 5-Gy IR the differences in gene expression were eliminated, apparently because ATM and Rad3-related (ATR) signaling was activated in AT lymphoblasts after the higher dose and similar checkpoint functions as in normal cells were initiated (30). In the present analysis, a 1.5-Gy IR dose that inhibited clonal expansion by 90% in AT fibroblasts and 40% in normal human fibroblasts (27) was selected for analysis of DNA damage checkpoint function and global changes in gene expression.…”

DNA Protein Kinase–Dependent G2 Checkpoint Revealed following Knockdown of Ataxia-Telangiectasia Mutated in Human Mammary Epithelial Cells

“…In addition, these cells were also sensitized to bleomycin sulfate but not to UV radiation. Much to our surprise, reduced expression of ATM in these mammary epithelial cells caused only a minor defect of the IR-induced G 2 checkpoint after exposure to 2-Gy radiation, less than the attenuation generally observed following a comparable dose exposure of fibroblast or lymphoblast cells from individuals with ataxia-telangiectasia (26,38).…”

Changes in Whole Blood Gene Expression after Computed Tomography in Children: A Pilot Study

“…We focused our study on 24 radiation responsive ERP29 ERP29 candidate genes because these genes were previously documented to be connected with functions intimately linked to cancer (Table 2). [18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37] Among the 24 genes, observations from previous studies noted post CT changes within 1 hour after radiation in 11 genes with 4 of them (ATM, ERP29, TP53, CDKN2A) showing post CT changes from very low radiation doses, as low as 0.1 Gy. Owing to their higher radiosensitivity, children are expected to react more sensitively than adults to the CT-induced radiation insult, and therefore, we included all 24 genes in our study, although some observations were reported longer than 1 hr post CT or after IR doses higher than those used in our study.…”