Portrait of transcriptional responses to ultraviolet and ionizing radiation in human cells

Abstract

To understand the human response to DNA damage, we used microarrays to measure transcriptional responses of 10 000 genes to ionizing radiation (IR) and ultraviolet radiation (UV). To identify bona fide responses, we used cell lines from 15 individuals and a rigorous statistical method, Significance Analysis of Microarrays (SAM). By exploring how sample number affects SAM, we rendered a portrait of the human damage response with a degree of accuracy unmatched by previous studies. By showing how SAM can be used to estimate the total number of responsive genes, we discovered that 24% of all genes respond to IR and 32% respond to UV, although most responses were less than 2-fold. Many genes were involved in known damage-response pathways for cell cycling and proliferation, apoptosis, DNA repair or the stress response. However, the majority of genes were involved in unexpected pathways, with functions in signal transduction, RNA binding and editing, protein synthesis and degradation, energy metabolism, metabolism of macromolecular precursors, cell structure and adhesion, vesicle transport, or lysosomal metabolism. Although these functions were not previously associated with the damage response in mammals, many were conserved in yeast. These insights reveal new directions for studying the human response to DNA damage.

SOG1: a master regulator of the DNA damage response in plants

“…This immediate transcriptional response to gamma irradiation is governed by ATM, but not by ATR (Culligan et al, 2006). In contrast to the robust transcriptional response in A. thaliana, microarray studies in human cells show that the magnitude of the change in the expression of irradiation-responsive genes is not as great (Rieger and Chu, 2004). Furthermore, few DNA repair genes are transcriptionally induced by gamma irradiation in human cells.…”

Low dose radiation response curves, networks and pathways in human lymphoblastoid cells exposed from 1 to 10cGy of acute gamma radiation

“…Many of these genes are known oncogenes. Our low-dose gene set included a strong apoptosis-associated gene, TNF receptor form 6 (TNFRSF6), that was previously associated with high-dose transcript response [20,72] for differing qualities of ionizing radiation [53]. Interestingly, we also identified two low-dose responsive genes thought to be associated with anti-apoptotic functions: CD83 and PTMA.…”

“…High-dose exposures (>2 Gy) are known to modulate the expression of genes associated with genotoxic and physiological stress responses including DNA damage sensing and repair, and immune response [11][12][13][14][15][16][17][18][19][20][21]. After high doses, the cellular decisions to initiate rescue or cell death appear to be mediated by signaling pathways and secondary messengers [22][23][24].…”

Is post-transcriptional stabilization, splicing and translation of selective mRNAs a key to the DNA damage response?

“…In a study of human lymphoblastoid cell lines from healthy adults, for example, Chu and colleagues found that thousands of mRNAs were up or downregulated after cells were exposed to ionizing radiation (IR) or ultraviolet light. 3 Similarly, as much as 20% of the genes in budding yeast showed a two-fold or greater change in mRNA levels in response to MMS treatment or ionizing radiation. 4 However, it would seem intuitively obvious that the last thing one would expect cells to do shortly after incurring significant DNA damage is to start transcribing new genes.…”