Transcriptional modulation induced by ionizing radiation: p53 remains a central player

Abstract

The cellular response to DNA damage is vital for maintaining genomic stability and preventing undue cell death or cancer formation. The DNA damage response (DDR), most robustly mobilized by double-strand breaks (DSBs), rapidly activates an extensive signaling network that affects numerous cellular systems, leading to cell survival or programmed cell death. A major component of the DDR is the widespread modulation of gene expression. We analyzed together six datasets that probed transcriptional responses to ionizing radiation (IR) - our novel experimental data and 5 published datasets - to elucidate the scope of this response and identify its gene targets. According to the mRNA expression profiles we recorded from 5 cancerous and non-cancerous human cell lines after exposure to 5 Gy of IR, most of the responses were cell line-specific. Computational analysis identified significant enrichment for p53 target genes and cell cycle-related pathways among groups of up-regulated and down-regulated genes, respectively. Computational promoter analysis of the six datasets disclosed that a statistically significant number of the induced genes contained p53 binding site signatures. p53-mediated regulation had previously been documented for subsets of these gene groups, making our lists a source of novel potential p53 targets. Real-time qPCR and chromatin immunoprecipitation (ChIP) assays validated the IR-induced p53-dependent induction and p53 binding to the respective promoters of 11 selected genes. Our results demonstrate the power of a combined computational and experimental approach to identify new transcriptional targets in the DNA damage response network.

Low doses of ionizing radiation induce immune-stimulatory responses in isolated human primary monocytes

“…5D) a pro-apoptotic gene, were shown to be exclusively induced in response to 1 Gy. These genes were extensively validated in response to ionizing radiation (40)(41)(42)(43)(44) and shown to be activated in response to p53 signaling (45), where as our results showed upregulation in the phosphorylated form of p53 in response to 1 Gy (Fig. 6).…”

Identification and Characterization of an Oocyte Factor Required for Porcine Nuclear Reprogramming

“…5G). Next we investigated expression of p53, which can be activated by the DNA damage response and which acts as a barrier to nuclear reprogramming (37)(38)(39). Expression of p53 was significantly increased in anti-VIM-NT embryos compared with Con-NT embryos at the four-cell stage at both mRNA and protein levels (Fig.…”

High-mobility group box 2 (HMGB2) modulates radioresponse and is downregulated by p53 in colorectal cancer cell

“…If the DNA damage is too severe to be recovered, genes regulating apoptotic cell death was also induced. 23 Because HMGB2 was required for protection cell from DNA damage and its knockdown sensitized cell to irradiation, we hypothesized HMGB2 might be induced by irradiation to protect cells from radiation induced death. So the effect of ionizing radiation on HMGB2 gene expression was investigated.…”