title: 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.
authors.affiliation: The David and Inez Myers Laboratory for Genetic Research, Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Room 1022, Tel Aviv 69978, Israel. rashrash@post.tau.ac.il
authors.forename: Sharon
authors.initials: S
authors.lastname: Rashi-Elkeles
authors.forename: Ran
authors.initials: R
authors.lastname: Elkon
authors.forename: Seagull
authors.initials: S
authors.lastname: Shavit
authors.forename: Yaniv
authors.initials: Y
authors.lastname: Lerenthal
authors.forename: Chaim
authors.initials: C
authors.lastname: Linhart
authors.forename: Ana
authors.initials: A
authors.lastname: Kupershtein
authors.forename: Ninette
authors.initials: N
authors.lastname: Amariglio
authors.forename: Gideon
authors.initials: G
authors.lastname: Rechavi
authors.forename: Ron
authors.initials: R
authors.lastname: Shamir
authors.forename: Yosef
authors.initials: Y
authors.lastname: Shiloh
mesh_terms: D045744:Cell Line, Tumor; D004249:DNA Damage / Q000528:radiation effects*; D030541:Databases, Genetic; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000528:radiation effects*; D053263:Gene Regulatory Networks; D006801:Humans; D015201:Meta-Analysis as Topic; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D011839:Radiation, Ionizing; D015398:Signal Transduction / Q000502:physiology; D014158:Transcription, Genetic / Q000528:radiation effects*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D016159:Tumor Suppressor Protein p53