Neurotoxic mechanisms of DNA damage: focus on transcriptional inhibition

Abstract

J. Neurochem. (2010) 114, 1537–1549. Abstract 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.

Effects of organic and inorganic mercury(II) on gene expression via DNA conformational changes

“…Although neuronal cells are less proliferative in adults, studies have revealed that DNA damage disrupts proper functioning of the nervous system (Hetman et al, 2010). Transcription from template DNA may be influenced by various DNA damage types, including strand breaks, base oxidation, and adduct formation.…”

Neurodegeneration-associated instability of ribosomal DNA.

“…DNA damage is well documented in neurodegeneration and in some cases it may be sufficient to cause disease [1,4]. Moreover, significant increases in oxidative DNA damage are known to occur in Alzheimer's disease, Parkinson's disease, and Dementia with Lewy Bodies [5,6].…”

“…Additionally, multiple congenital diseases involving mutations of DNA repair proteins often involve neurodegeneration. These diseases include ataxia with oculomotor apraxia 1, spinocerebellar ataxia with axonal neuropathy 1 and xeroderma pigmentosum [1,4,[7][8][9]. Moreover, DNA damage is well known to induce cell death by a number of mechanisms including inhibition of nucleolar transcription and genomic instability [4,10].…”

Involvement of Histone PTMs in DNA Repair Processes in Relation to Age-Associated Neurodegenerative Disease

“…brain cells, as well as transcriptional inhibition of the vulnerable genes involved in learning, memory and neuronal survival (Hetman et al, 2010). All these contribute to the pathogenesis of age related neurodegenerative diseases.…”