The role of the DNA damage response in neuronal development, organization and maintenance

The DNA damage response is a key factor in the maintenance of genome stability. As such, it is a central axis in sustaining cellular homeostasis in a variety of contexts: development, growth, differentiation, and maintenance of the normal life cycle of the cell. It is now clear that diverse mechanisms encompassing cell cycle regulation, repair pathways, many aspects of cellular metabolism, and cell death are inter-linked and act in consort in response to DNA damage. Defects in the DNA damage response in proliferating cells can lead to cancer while defects in neurons result in neurodegenerative pathologies. Neurons are highly differentiated, post-mitotic cells that cannot be replenished after disease or trauma. Their high metabolic activity that generates large amounts of reactive oxygen species with DNA damaging capacity and their intense transcriptional activity increase the potential for damage of their genomic DNA. Neurons ensure their longevity and functionality in the face of these threats by elaborate mechanisms that defend the integrity of their genome. This review focuses on the DNA damage response in neuronal cells and points to the importance of this elaborate network to the integrity of the nervous system from its early development and throughout the lifetime of the organism. (C) 2008 Published by Elsevier B.V.