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The protection of genomic integrity is a major challenge for living cells that are continuously exposed to endogenous and environmental DNA-damaging insults. To cope with the consequences of DNA lesions which interfere with essential DNA-dependent processes including transcription and replication, cells are equipped with an efficient defense mechanism termed the DNA damage response. Its function is to eliminate DNA damage through DNA repair and to remove cells with incurred DNA damage by apoptosis. The DNA damage response has been investigated mainly in proliferating cells, in which the cell cycle machinery is integrated with the DNA damage signaling. Our recent studies suggest that the cell cycle machinery is involved in DNA damage response of postmitotic neurons. Given a high metabolic rate, continuous exposure to oxidative stress and extensive gene transcription activity, the importance of the DNA damage response and the integrated cell cycle signaling for maintaining genomic stability in neurons cannot be overemphasized. The suppression of cell cycle activation is considered neuroprotective, especially in experimental models of stroke. The present review discusses the importance of DNA damage response for postmitotic neurons and the mechanisms of its dysfunction leading to different neurodegenerative disorders. In this regard, a better understanding of the mechanisms underlying DNA damage response in neurons may have important therapeutic implications for different neurodegenerative diseases.

Increasing evidence indicates that maintenance of neuronal homeostasis involves the activation of the cell cycle machinery in postmitotic neurons. Our recent findings suggest that cell cycle activation is essential for DNA damage-induced neuronal apoptosis. However, whether the cell division cycle also participates in DNA repair and survival of postmitotic, terminally differentiated neurons is unknown. Here, we tested the hypothesis that G(1) phase components contribute to the repair of DNA and are involved in the DNA damage response of postmitotic neurons. In cortical terminally differentiated neurons, treatment with subtoxic concentrations of hydrogen peroxide (H(2)O(2)) caused repairable DNA double strand breaks (DSBs) and the activation of G(1) components of the cell cycle machinery. Importantly, DNA repair was attenuated if cyclin-dependent kinases CDK4 and CDK6, essential elements of G(0) --> G(1) transition, were suppressed. Our data suggest that G(1) cell cycle components are involved in DNA repair and survival of postmitotic neurons.

A chronic imbalance in DNA precursors, caused by one-carbon metabolism impairment, can result in a deficiency of DNA repair and increased DNA damage. Although indirect evidence suggests that DNA damage plays a role in neuronal apoptosis and in the pathogenesis of neurodegenerative disorders, the underlying mechanisms are poorly understood. In particular, very little is known about the role of base excision repair of misincorporated uracil in neuronal survival. To test the hypothesis that repair of DNA damage associated with uracil misincorporation is critical for neuronal survival, we employed an antisense (AS) oligonucleotide directed against uracil-DNA glycosylase encoded by the UNG gene to deplete UNG in cultured rat hippocampal neurons. AS, but not a scrambled control oligonucleotide, induced apoptosis, which was associated with DNA damage analyzed by comet assay and up-regulation of p53. UNG mRNA and protein levels were decreased within 30 min and were undetectable within 6-9 h of exposure to the UNG AS oligonucleotide. Whereas UNG expression is significantly higher in proliferating as compared with nonproliferating cells, such as neurons, the levels of UNG mRNA were increased in brains of cystathionine beta-synthase knockout mice, a model for hyperhomocysteinemia, suggesting that one-carbon metabolism impairment and uracil misincorporation can induce the up-regulation of UNG expression.