Neurotoxic mechanisms of DNA damage: focus on transcriptional inhibition.

Although DNA damage-induced neurotoxicity is implicated in various pathologies of the nervous system, its underlying mechanisms are not completely understood. Transcription is a DNA transaction that is highly active in the nervous system. In addition to its direct role in expression of the genetic information, transcription contributes to DNA damage detection and repair as well as chromatin organization including biogenesis of the nucleolus. Transcription is inhibited by DNA single-strand breaks and DNA adducts. Hence, transcription inhibition may be an important contributor to the neurotoxic consequences of such types of DNA damage. This review discusses the existing evidence in support of the latter hypothesis. The presented literature suggests that neuronal DNA damage interferes with the RNA-Polymerase-2-dependent transcription of genes encoding proteins with critical functions in neurotransmission and intracellular signaling. The latter category includes extracellular signal-regulated kinase-1/2 mitogen-activated protein kinase phosphatases whose lowered expression results in chronic activation of extracellular signal-regulated kinase-1/2 and its reduced responsiveness to physiological stimuli. Conversely, DNA damage-induced inhibition of RNA-Polymerase-1 and the subsequent disruption of the nucleolus induce p53-mediated apoptosis of developing neurons. Finally, decreasing nucleolar transcription may link DNA damage to chronic neurodegeneration in adults.