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Review
, 114 (6), 1537-49

Neurotoxic Mechanisms of DNA Damage: Focus on Transcriptional Inhibition

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Review

Neurotoxic Mechanisms of DNA Damage: Focus on Transcriptional Inhibition

Michal Hetman et al. J Neurochem.

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.

Figures

Figure 1
Figure 1
Functions of the transcription. While gene expression is the most recognized role of the transcription, that process has also other functions which are not directly related to gene expression (see text for details).
Figure 2
Figure 2
Hypothetical model of transcriptional inhibition observed in aging human cerebral cortex as proposed by Li, Yankner et al. (2004). Aging-associated accumulation of unrepaired oxidative damage to guanine bases (8-oxoG) disrupts interaction of the promoters with some transcription factors (such as a hypothetical TF-Y) reducing transcription initiation (see text for details).
Figure 3
Figure 3
Hypothetical model explaining DNA damage-associated activation of the neuronal ERK1/2 signaling pathway. In neurons, synaptic activity-induced increase of cytosolic [Ca2+] or neurotrophin-mediated activation of tyrosine receptor kinases (Trks) initiate the signaling by the kinase cascade of Raf-MKK1/2-ERK1/2. Thus, ERK1/2 is activated following its phosphorylation by MKK1/2. Conversely, its inactivation is carried out by phosphatases of phospho-ERK1/2 (PPE). The targets of activated ERK1/2 include transcriptional regulators that induce several PPEs terminating ERK1/2 signaling. DNA damage disrupts ERK inactivation by reducing transcription of PPEs (see text for details).
Figure 4
Figure 4
The kinetical model of dysregulated ERK signaling following DNA damage-associated loss of ERK phosphatases. A, The differential equation model presented in top panel is used to describe the longitudinal relation between Raf (r), MKK1/2 (x), ERK1/2 (y), and PPE (z). Dotted quantities indicate derivatives with respect to time. The kinetic constants were picked so as to approximate the published experimental data (Gozdz et al. 2008; α1=0.2, α2=0.1, β1=0.2, β2=0.1, γ1=0.1, γ2=0.2). The additional constants A (=10) and B (=5) represent the amounts of MKK and ERK at the inception of the signaling process; at that time, the amounts of Raf and PPE were assumed to be 0.1 and 3, respectively. B, C, Trajectories of the differential equation representing the changes in the amounts of RAF (r), MKK (x), ERK (y), and PPE (z) over 60 hour period of time. In B, we take δ=0, i.e., assume that PPE does not decrease in time from its initial amount. In C, we take δ=0.0916 and thus allow PPE to decrease in time. The rate of the decrease is fitted to be consistent with experimental results indicating a three-fold decrease in PPE activity for phospho-Tyr185-ERK1/2 after Treating cultured rat cortical neurons with 10 μg/ml cisplatin for 12 hr (marked as the black point on the PPE graph, (Gozdz et al. 2008)). With constant PPE activity, ERK and phospho-ERK levels remain at equilibrium (B). Upon PPE decline, all ERK is converted to phospho-ERK suggesting loss of ERK responsiveness to physiological stimuli and, therefore, functional inactivation of this signaling pathway (C).
Figure 5
Figure 5
Hypothetical model of nucleolar involvement in neuronal response to DNA damage. DNA damage blocks the RNAPol1-mediated transcription of rDNA disrupting structural integrity of the nucleolus. Thus, functions of that nuclear domain are compromised leading to disinhibition of p53, disturbed processing of various non-rRNA species and reduced ribosomal biogenesis. In developing neurons that are challenged with DNA damage, such a nucleolar stress may activate the p53-dependent apoptotic program whose execution requires induction of the RNAPol2-transcribed killer genes (Kalita et al. 2008). In mature neurons, which are more resistant to apoptosis, chronic consequences of nucleolar dysfunction may include atrophy, loss of synapses/neurites and reduced synaptic plasticity (see text for details).

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