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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

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Abstract

Neurons are very sensitive to DNA damage induced by endogenous and exogenous genotoxic agents, as defective DNA repair can lead to neurodevelopmental disorders, brain tumors and neurodegenerative diseases with severe clinical manifestations. Understanding the impact of DNA damage/repair mechanisms on the nuclear organization, 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 γH2AX, 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 pathway 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 transcription rate in neurons.

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Acknowledgments

The authors wish to thank Saray Pereda for technical assistance. This work was supported by the following grants: “Dirección General de Investigación” (BFU2008-00175), “Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas” (CIBERNED; CB06/05/0037) Spain, and “Proyecto I+D+I de la Comunidad de Cantabria” (FMV-UC 09/02) Santander, Spain.

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Authors and Affiliations

  1. Departamento de Anatomía y Biología Celular, “Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED)”, Universidad de Cantabria, IFIMAV, Santander, Spain

    Iñigo Casafont, Ana Palanca, Maria T. Berciano & Miguel Lafarga

  2. Departamento de Biología Molecular, Centro de Biología Molecular “Severo Ochoa”, Universidad Autónoma de Madrid, Madrid, Spain

    Vanesa Lafarga

  3. Instituto de Investigación Sanitaria La Princesa, Madrid, Spain

    Vanesa Lafarga

  4. Department of Anatomy and Cell Biology, Faculty of Medicine, University of Cantabria, Avd. Cardenal Herrera Oria s/n, 39011, Santander, Spain

    Miguel Lafarga

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  1. Iñigo Casafont
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  2. Ana Palanca
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  3. Vanesa Lafarga
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  4. Maria T. Berciano
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  5. Miguel Lafarga
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Corresponding author

Correspondence to Miguel Lafarga.

Additional information

I. Casafont and A. Palanca contributed equally to the work reported here.

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Casafont, I., Palanca, A., Lafarga, V. et al. 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. Acta Neuropathol 122, 481–493 (2011). https://doi.org/10.1007/s00401-011-0869-0

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