title: Nucleolar disruption and apoptosis are distinct neuronal responses to etoposide-induced DNA damage.
abstract: Although DNA damaging topoisomerase inhibitors induce apoptosis in developing neurons, their effects on adult neurons have not yet been characterized. We report a blockage of RNA-Polymerase-1-driven transcription and nucleolar stress in neocortical neurons of adult rats after intracarotid injection of the DNA-topoisomerase-2 inhibitor, etoposide. Intracerebroventricular injection of etoposide induced a similar response in neonatal rats. In contrast, etoposide triggered neuronal apoptosis in the neonates, but not the adults. Nucleolar disruption and apoptosis were also observed in etoposide-challenged cultured cortical neurons from newborn rats. In that system, activation of the DNA double strand break signaling kinase ataxia telangiectasia-mutated protein kinase, p53 and p53-dependent apoptosis required lower etoposide concentrations than did the p53-independent induction of nucleolar stress. These distinct responses may be coupled to different forms of etoposide-induced DNA damage. Indeed, double strand breaks by the over-expressed endonuclease I-Ppo1 were sufficient to induce p53-dependent apoptosis. Moreover, nucleolar transcription was insensitive to such damage implying single strand breaks and/or topoisomerase-2-DNA adducts as triggers of nucleolar stress. Because nucleolar stress is not age-restricted, it may underlie non-apoptotic neurotoxicity of chemotherapy- or neurodegeneration-associated DNA damage by reducing ribosomal biogenesis in adult brain. Conversely, nucleolar insensitivity to double strand breaks likely contributes to mature neuron tolerance of such lesions.
authors.affiliation: Kentucky Spinal Cord Injury Research Center and the Departments of Neurological Surgery, University of Louisville, Louisville, Kentucky 40292, USA.
authors.forename: Maciej
authors.initials: M
authors.lastname: Pietrzak
authors.forename: Scott C
authors.initials: SC
authors.lastname: Smith
authors.forename: Justin T
authors.initials: JT
authors.lastname: Geralds
authors.forename: Theo
authors.initials: T
authors.lastname: Hagg
authors.forename: Cynthia
authors.initials: C
authors.lastname: Gomes
authors.forename: Michal
authors.initials: M
authors.lastname: Hetman
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000633:toxicity*; D064007:Ataxia Telangiectasia Mutated Proteins; D002339:Carotid Arteries; D018797:Cell Cycle Proteins / Q000378:metabolism; D002466:Cell Nucleolus / Q000187:drug effects* / Q000648:ultrastructure; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D033481:Chromosomes, Mammalian / Q000235:genetics; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation; D005047:Etoposide / Q000008:administration & dosage / Q000633:toxicity*; D007269:Injections, Intra-Arterial; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D009474:Neurons / Q000187:drug effects* / Q000648:ultrastructure; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012318:RNA Polymerase I / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D059005:Topoisomerase II Inhibitors / Q000633:toxicity*; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D059005:Topoisomerase II Inhibitors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D005047:Etoposide; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases; D012318:RNA Polymerase I