title: Transcriptional and post-transcriptional regulation of the ionizing radiation response by ATM and p53.
abstract: In response to ionizing radiation (IR), cells activate a DNA damage response (DDR) pathway to re-program gene expression. Previous studies using total cellular RNA analyses have shown that the stress kinase ATM and the transcription factor p53 are integral components required for induction of IR-induced gene expression. These studies did not distinguish between changes in RNA synthesis and RNA turnover and did not address the role of enhancer elements in DDR-mediated transcriptional regulation. To determine the contribution of synthesis and degradation of RNA and monitor the activity of enhancer elements following exposure to IR, we used the recently developed Bru-seq, BruChase-seq and BruUV-seq techniques. Our results show that ATM and p53 regulate both RNA synthesis and stability as well as enhancer element activity following exposure to IR. Importantly, many genes in the p53-signaling pathway were coordinately up-regulated by both increased synthesis and RNA stability while down-regulated genes were suppressed either by reduced synthesis or stability. Our study is the first of its kind that independently assessed the effects of ionizing radiation on transcription and post-transcriptional regulation in normal human cells.
authors.affiliation: Department of Radiation Oncology, University of Michigan Comprehensive Cancer Center, Translational Oncology Program and Center for RNA Biomedicine, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Ishwarya
authors.initials: I
authors.lastname: Venkata Narayanan
authors.affiliation: Department of Radiation Oncology, University of Michigan Comprehensive Cancer Center, Translational Oncology Program and Center for RNA Biomedicine, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Michelle T
authors.initials: MT
authors.lastname: Paulsen
authors.affiliation: Department of Radiation Oncology, University of Michigan Comprehensive Cancer Center, Translational Oncology Program and Center for RNA Biomedicine, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Karan
authors.initials: K
authors.lastname: Bedi
authors.affiliation: Department of Radiation Oncology, University of Michigan Comprehensive Cancer Center, Translational Oncology Program and Center for RNA Biomedicine, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Nathan
authors.initials: N
authors.lastname: Berg
authors.affiliation: Department of Radiation Oncology, University of Michigan Comprehensive Cancer Center, Translational Oncology Program and Center for RNA Biomedicine, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Emily A
authors.initials: EA
authors.lastname: Ljungman
authors.affiliation: IFOM - The FIRC Institute of Molecular Oncology Foundation, Milan, Italy.|Istituto di Genetica Molecolare, Consiglio Nazionale delle Ricerche, Pavia, Italy.
authors.forename: Sofia
authors.initials: S
authors.lastname: Francia
authors.affiliation: Department of Radiation Oncology, University of Michigan Comprehensive Cancer Center, Translational Oncology Program and Center for RNA Biomedicine, University of Michigan, Ann Arbor, Michigan, USA.|Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA.
authors.forename: Artur
authors.initials: A
authors.lastname: Veloso
authors.affiliation: Department of Radiation Oncology, University of Michigan Comprehensive Cancer Center, Translational Oncology Program and Center for RNA Biomedicine, University of Michigan, Ann Arbor, Michigan, USA.|Departments of Pathology and Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Magnuson
authors.affiliation: IFOM - The FIRC Institute of Molecular Oncology Foundation, Milan, Italy.|Istituto di Genetica Molecolare, Consiglio Nazionale delle Ricerche, Pavia, Italy.
authors.forename: Fabrizio d'Adda
authors.initials: FD
authors.lastname: di Fagagna
authors.affiliation: Departments of Pathology and Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Wilson
authors.affiliation: Department of Radiation Oncology, University of Michigan Comprehensive Cancer Center, Translational Oncology Program and Center for RNA Biomedicine, University of Michigan, Ann Arbor, Michigan, USA.|Department of Environmental Health Sciences, School of Public Health, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Mats
authors.initials: M
authors.lastname: Ljungman
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism*; D002460:Cell Line; D004249:DNA Damage / Q000528:radiation effects; D004742:Enhancer Elements, Genetic; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000528:radiation effects*; D006801:Humans; D012323:RNA Processing, Post-Transcriptional; D020871:RNA Stability / Q000528:radiation effects; D011839:Radiation, Ionizing; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D016159:Tumor Suppressor Protein p53; D064007:Ataxia Telangiectasia Mutated Proteins