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.