ORIGINAL PAPER Effect of ionizing radiation in sensory ganglion neurons: organization and dynamics of nuclear compartments of DNA damage/repair and their relationship with transcription and cell cycle In ˜ igo Casafont • Ana Palanca • Vanesa Lafarga • Maria T. Berciano • Miguel Lafarga Received: 14 July 2011 / Revised: 31 August 2011 / Accepted: 2 September 2011 / Published online: 14 September 2011 Ó Springer-Verlag 2011 Abstract Neurons are very sensitive to DNA damage induced by endogenous and exogenous genotoxic agents, as defective DNA repair can lead to neurodevelopmental dis- orders, brain tumors and neurodegenerative diseases with severe clinical manifestations. Understanding the impact of DNA damage/repair mechanisms on the nuclear organiza- tion, particularly on the regulation of transcription and cell cycle, is essential to know the pathophysiology of defective DNA repair syndromes. In this work, we study the nuclear architecture and spatiotemporal organization of chromatin compartments involved in the DNA damage response (DDR) in rat sensory ganglion neurons exposed to X-ray irradiation (IR). We demonstrate that the neuronal DDR involves the formation of two categories of DNA-damage processing chromatin compartments: transient, disappearing within the 1 day post-IR, and persistent, where unrepaired DNA is accumulated. Both compartments concentrate components of the DDR pathway, including cH2AX, pATM and 53BP1. Furthermore, DNA damage does not induce neuronal apoptosis but triggers the G0–G1 cell cycle phase transition, which is mediated by the activation of the ATM-p53 path- way and increased protein levels of p21 and cyclin D1. Moreover, the run on transcription assay reveals a severe inhibition of transcription at 0.5 h post-IR, followed by its rapid recovery over the 1 day post-IR in parallel with the progression of DNA repair. Therefore, the response of healthy neurons to DNA damage involves a transcription- and cell cycle-dependent but apoptosis-independent process. Furthermore, we propose that the segregation of unrepaired DNA in a few persistent chromatin compartments preserves genomic stability of undamaged DNA and the global tran- scription rate in neurons. Keywords DNA damage and repair  Neurons  Nuclear compartments  Cell cycle reactivation  Genotoxic stress  DNA damage and transcription Introduction The cell nucleus is highly organized in nuclear compartments which are involved in replication, transcription and repair of DNA, as well as in RNA processing and transport. Nuclear architecture, particularly the chromatin configuration, has a profound impact on nuclear functions [32]. Mammalian sen- sory ganglion neurons have a predominant active chromatin configuration (euchromatin), whereas the repressed chromatin is basically restricted to a few centromeric and telomeric heterochromatin aggregates [39, 48]. This chromatin config- uration clearly correlates with the high transcriptional activity I. Casafont and A. Palanca contributed equally to the work reported here. I. Casafont  A. Palanca  M. T. Berciano  M. Lafarga Departamento de Anatomı ´a y Biologı ´a Celular, ‘‘Centro de Investigacio ´n Biome ´dica en Red sobre Enfermedades Neurodegenerativas (CIBERNED)’’, Universidad de Cantabria, IFIMAV, Santander, Spain V. Lafarga Departamento de Biologı ´a Molecular, Centro de Biologı ´a Molecular ‘‘Severo Ochoa’’, Universidad Auto ´noma de Madrid, Madrid, Spain V. Lafarga Instituto de Investigacio ´n Sanitaria La Princesa, Madrid, Spain M. Lafarga (&) Department of Anatomy and Cell Biology, Faculty of Medicine, University of Cantabria, Avd. Cardenal Herrera Oria s/n, 39011 Santander, Spain e-mail: lafargam@unican.es 123 Acta Neuropathol (2011) 122:481–493 DOI 10.1007/s00401-011-0869-0